Beta-hairpin peptidomimetics

ABSTRACT

Beta-hairpin peptidomimetics of the general formula (I), cyclo[P 1 -P 2 -P 3 -P 4 -P 5 -P 6 -P 7 -P 8 -P 9 -P 10 -P 11 -P 12 -T 1 -T 2 ], and pharmaceutically acceptable salts thereof, with P 1  to P 12 , T 1  and T 2  being elements as defined in the description and the claims, have Gram-negative antimicrobial activity to e.g. inhibit the growth or to kill microorganisms such as  Klebsiella pneumoniae  and/or  Acinetobacter baumannii  and/or  Escherichia coli.    
     They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials. 
     These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

This application is a Divisional of co-pending U.S. patent applicationSer. No. 15/515,417 filed on Mar. 29, 2017, which is the National Phaseof PCT International Application No. PCT/EP2015/025068, filed on Sep.29, 2015, which claims priority to European Patent Application No.14003372.1 filed on Sep. 30, 2014. The entire contents of all of theabove applications are hereby incorporated by reference into the presentapplication.

The present invention provides β-hairpin peptidomimetics havingGram-negative antimicrobial activity.

The β-hairpin peptidomimetics of the invention are compounds of thegeneral formula (I),cyclo[P¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²], andpharmaceutically acceptable salts thereof, with P¹ to P¹², T¹ and T²being elements as described herein below.

In addition, the present invention provides an efficient syntheticprocess by which these compounds can, if desired, be made in parallellibrary-format. Moreover, the β-hairpin peptidomimetics of the inventionshow improved efficacy, reduced hemolysis of red blood cells and reducedor no cytotoxicity.

A major cause of death worldwide and a leading cause of mortality indeveloped countries are infectious diseases. They result from thepresence of pathogenic microbial agents including pathogenic viruses andpathogenic bacteria. The problem of bacterial resistance to establishedantibiotics has stimulated intense interest in developing novelantimicrobial agents with new modes of action (D. Obrecht, J. A.Robinson, F. Bernadini, C. Bisang, S. J. DeMarco, K. Moehle, F. O.Gombert, Curr. Med. Chem. 2009, 16, 42-65; H. Breithaupt, Nat.Biotechnol. 1999, 17, 1165-1169).

A growing unmet medical need is represented by Gram-negative bacteriacausing 60% of nosocomial pneumonias (R. Frechette, Ann. Rep. Med.Chem., Elsevier, 2007, 349-64). Extended spectrum beta lactamase(ESBL)-producing Gram-negative bacteria have also compromised theutility of many front-line beta-lactam drugs (S. J. Projan, P. A.Bradford, Curr. Opin. Microbiol., 2007, 10, 441). The lack of suitablenew compounds is forcing clinicians to use previously discardedantibiotics like colistin, despite well-known toxicity problems (M. E.Falagas, S. K. Kasiakou, Crit. Care, 2006, 10, R 27). Therefore, novelapproaches are needed to treat inter alia resistant strains ofKlebsiella pneumoniae, Acinetobacter baumannii and Escherichia coli (H.W. Boucher, G. H. Talbot, J. S. Bradley, J. E. Edwards Jr, D. Gilbert,L. B. Rice, M. Scheld, B. Spellberg, J. Bartlett, IDSA Report onDevelopment Pipeline, CID 2009, 48, 1).

One emerging class of antibiotics is based on naturally occurringcationic peptides (T. Ganz, R. I. Lehrer, Mol. Medicine Today 1999, 5,292-297; R. M. Epand, H. J. Vogel, Biochim. Biophys. Acta 1999, 1462,11-28). These include disulfide-bridged β-hairpin and β-sheet peptides(such as the protegrins [V. N. Kokryakov, S. S. L. Harwig, E. A.Panyutich, A. A. Shevchenko, G. M. Aleshina, O. V. Shamova, H. A.Korneva, R. I. Lehrer, FEBS Lett. 1993, 327, 231-236], tachyplesins [T.Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M.Niwa, T. Takao, Y. Shimonishi, J. Biol. Chem. 1988, 263, 16709-16713],and the defensins [R. I. Lehrer, A. K. Lichtenstein, T. Ganz, Annu. Rev.Immunol. 1993, 11, 105-128], amphipathic α-helical peptides (e.g.cecropins, dermaseptins, magainins, and mellitins [A. Tossi, L. Sandri,A. Giangaspero, Biopolymers 2000, 55, 4-30]), as well as other linearand loop-structured peptides. Although the mechanisms of action ofantimicrobial cationic peptides are not yet fully understood, theirprimary site of interaction is the microbial cell membrane (H. W. Huang,Biochemistry 2000, 39, 8347-8352). Upon exposure to these agents, thecell membrane undergoes permeabilization, which is followed by rapidcell death. However, more complex mechanisms of action, for example,involving receptor-mediated signaling, cannot presently be ruled out (M.Wu, E. Maier, R. Benz, R. E. Hancock, Biochemistry 1999, 38, 7235-7242).

In the compounds described below, a strategy is introduced to stabilizeβ-hairpin conformations in backbone-cyclic cationic peptide mimeticsexhibiting Gram-negative antimicrobial activity, in particular againstGram-negative pathogens of the so-called ESKAPE pathogens (L. B. Rice,J. Infect. Dis. 2008, 197, 1079). This involves transplanting thehairpin sequence onto a template, whose function is to restrain thepeptide loop backbone into hairpin geometry. The introduction ofadditional interstrand (0-strand) linkages may further enhance therigidity of the hairpin.

Template-bound hairpin mimetic peptides have been described in theliterature (D. Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441) and theability to generate β-hairpin peptidomimetics using combinatorial andparallel synthesis methods has now been established (L. Jiang, K.Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000,83, 3097-3112). Antibacterial template-fixed peptidomimetics and methodsfor their synthesis have been described in international patentapplications WO02/070547 A1, WO2004/018503 A1, WO2007/079605 A2 andWO2012/016595 A1 but these molecules do not show Gram-negativeantimicrobial activity having high potency against Klebsiello pneumoniaeand/or Acinetobacter baumannii and/or Escherichia coli.

The present invention relates to novel β-hairpin peptidomimetics offormula (I),cyclo[P¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²]  (I)

wherein the single elements T or P are connected in either directionfrom the carbonyl (C═O) point of attachment to the nitrogen (N) of thenext element and wherein

-   T¹ is a naturally or non-naturally occurring D α-amino acid    containing an optionally substituted side-chain which forms a four-    or five-membered heterocycle or a bicyclic system comprising the    α-carbon and the α-amino atom; or a naturally or non-naturally    occurring D α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain; or a naturally or non-naturally    occurring aliphatic L α-amino acid containing in total 1 to 25    carbon- and/or heteroatoms in a single side-chain being substituted    at the α-amino atom by an aliphatic chain containing in total 1 to    25 carbon- and/or heteroatoms; or glycine being substituted at the    α-amino atom by an aliphatic chain containing in total 1 to 25    carbon- and/or heteroatoms;-   T² is a naturally or non-naturally occurring L α-amino acid    containing an optionally substituted side-chain which forms a five-    or six-membered heterocycle or a bicyclic system comprising the    α-carbon and the α-amino atom; or a naturally or non-naturally    occurring aliphatic L α-amino acid containing in total 1 to 25    carbon- and/or heteroatoms in a single side-chain; or a naturally or    non-naturally occurring aromatic L α-amino acid containing in total    1 to 25 carbon- and/or heteroatoms in a single side-chain; or a    naturally or non-naturally occurring basic L α-amino acid containing    in total 1 to 25 carbon- and/or heteroatoms in a single side-chain    comprising at least one amino function;-   P¹ is a naturally or non-naturally occurring aliphatic L α-amino    acid containing in total 1 to 25 carbon- and/or heteroatoms in a    single side-chain; or a naturally or non-naturally occurring    aromatic L α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain; or a naturally or non-naturally    occurring L α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain comprising at least one urea    function, amide function, ester function, sulfone function or ether    function; or a naturally or non-naturally occurring alcoholic L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain;-   P² is Gly; or a naturally or non-naturally occurring L α-amino acid    containing in total 1 to 25 carbon- and/or heteroatoms in a single    side-chain;-   P³, P⁸ and P¹⁰ are independently    -   a naturally or non-naturally occurring aliphatic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain; or a naturally or non-naturally occurring        aromatic L α-amino acid containing in total 1 to 25 carbon-        and/or heteroatoms in a single side-chain;-   P⁴ is a naturally or non-naturally occurring aliphatic L α-amino    acid containing in total 1 to 25 carbon- and/or heteroatoms in a    single side-chain; or a naturally or non-naturally occurring basic L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain comprising at least one amino function; or a    naturally or non-naturally occurring L α-amino acid containing in    total 1 to 25 carbon- and/or heteroatoms in a single side-chain    comprising at least one urea function, amide function, ester    function, sulfone function or ether function; or a naturally or    non-naturally occurring alcoholic L α-amino acid containing in total    1 to 25 carbon- and/or heteroatoms in a single side-chain;-   P⁵ is a naturally or non-naturally occurring basic L α-amino acid    containing in total 1 to 25 carbon- and/or heteroatoms in a single    side-chain comprising at least one amino function; or a naturally or    non-naturally occurring L α-amino acid containing in total 1 to 25    carbon- and/or heteroatoms in a single side-chain comprising at    least one urea function, amide function, ester function, sulfone    function or ether function; or a naturally or non-naturally    occurring alcoholic L α-amino acid containing in total 1 to 25    carbon- and/or heteroatoms in a single side-chain;-   P⁶ is Gly; or a naturally or non-naturally occurring basic D or L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain comprising at least one amino function;-   P⁷ is a naturally or non-naturally occurring basic L α-amino acid    containing in total 1 to 25 carbon- and/or heteroatoms in a single    side-chain comprising at least one amino function;-   P⁹, P¹¹ and P¹² are independently    -   a naturally or non-naturally occurring L α-amino acid containing        in total 1 to 25 carbon- and/or heteroatoms in a single        side-chain;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together can form    naturally or non-naturally cross-linking D or L α-amino acids    containing each in total 1 to 12 carbon- and/or heteroatoms in a    single side-chain which together are connecting P² and P¹¹ and/or P⁴    and P⁹ by covalent interaction (interstrand linkage);

or a tautomer or rotamer thereof, or a salt, or a hydrate or solvatethereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is a naturally or non-naturally occurring aromatic L α-amino        acid containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain; or a naturally or non-naturally occurring        basic L α-amino acid containing in total 1 to 25 carbon- and/or        heteroatoms in a single side-chain comprising at least one amino        function;

or

-   P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures of one    of the formulae AA13; or AA13^(D); with Z being, with the proviso of    containing less than 25 carbon- and/or heteroatoms,    —(CH₂)_(n)—S—S—(CH₂)_(m)—; —(CH₂)_(n)CONR¹(CH₂)_(m)—;    —(CH₂)_(n)NR¹CO(CH₂)_(m)—; or —(CH₂)_(n)NR¹CONR²(CH₂)_(m)—;

or

-   P² is a naturally or non-naturally occurring aromatic L α-amino acid    containing in total 1 to 25 carbon- and/or heteroatoms in a single    side-chain; or a naturally or non-naturally occurring basic L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain comprising at least one amino function; and    P⁴ and P⁹ taken together form interstrand linking bis(amino    acid)-structures of one of the formulae AA13; or AA13^(D); with Z    being, with the proviso of containing less than 25 carbon- and/or    heteroatoms, —(CH₂)_(n)—S—S—(CH₂)_(m)—; —(CH₂)_(n)CONR¹(CH₂)_(m)—;    —(CH₂)_(n) NR¹CO(CH₂)_(m)—; or —(CH₂)_(n)NR¹CONR²(CH₂)_(m)—;

and

-   T¹ is a naturally or non-naturally occurring D α-amino acid    containing an optionally substituted side-chain which forms a four-    or five-membered heterocycle or a bicyclic system comprising the    α-carbon and the α-amino atom;

then

-   T² is an L α-amino acid of formula AA10 with R^(Am) being, with the    proviso of containing less than 26 carbon- and/or heteroatoms,    —(CR¹R¹³)_(q)NR²C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶; or    —(CH₂)_(n)S(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶;

and with the further proviso that

if no interstrand linkage is formed;

and

-   T¹ is a naturally or non-naturally occurring D α-amino acid    containing an optionally substituted side-chain which forms a    five-membered heterocycle or a bicyclic system comprising the    α-carbon and the α-amino atom;

and

-   P² is Gly; or a naturally or non-naturally occurring aliphatic L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain; a naturally or non-naturally occurring L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain comprising at least one urea function, amide    function, ester function, sulfone function or ether function; or a    naturally or non-naturally occurring alcoholic L α-amino acid    containing in total 1 to 25 carbon- and/or heteroatoms in a single    side-chain;

then

-   T² is a naturally or non-naturally occurring aliphatic L α-amino    acid containing in total 1 to 25 carbon- and/or heteroatoms in a    single side-chain; or a naturally or non-naturally occurring    aromatic L α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain; or a naturally or non-naturally    occurring basic L α-amino acid containing in total 1 to 25 carbon-    and/or heteroatoms in a single side-chain comprising at least one    amino function.

A particular embodiment of the present invention relates to compoundsaccording to general formula (I), wherein

-   T¹ is an D α-amino acid residue of one of the formulae

-   or an L α-amino acid residue of one of formulae

-   T² is an L α-amino acid residue of one of the formulae

-   P¹ is an L α-amino acid residue of one of the formulae

-   P² is Gly; or an L α-amino acid residue of one of the formulae

-   P³, P⁸ and P¹⁰ are independently an L α-amino acid residue of one of    the formulae

-   P⁴ is an L α-amino acid residue of one of the formulae

-   P⁵ is an L α-amino acid residue of one of the formulae

-   P⁶ is Gly; or an L or D α-amino acid residue of formula

-   P⁷ is an L α-amino acid residue of formula

-   P⁹, P¹¹ and P¹² are independently an L α-amino acid residue of one    of the formulae

-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together can form    interstrand linking bis(amino acid)-structures of one of the    formulae

-   -   based on the linkage of two L- or D-α-amino acid residues;

-   R^(Alk) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, C₁₋₁₂-alkyl; C₂₋₁₂-alkenyl; cycloalkyl;    cycloalkyl-C₁₋₆-alkyl; or C₁₋₆-alkoxy-C₁₋₆-alkyl;

-   R^(Ar) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R⁴)_(n)R¹⁹; —(CH₂)_(n)O(CH₂)_(m)R¹⁹;    —(CH₂)_(n)S(CH₂)_(m)R¹⁹; or —(CH₂)_(n)NR¹⁴(CH₂)_(m)R¹⁹;

-   R^(Am) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R¹³)_(q)NR¹⁵R¹⁶; —(CH₂)_(q)C(═NR¹³)NR¹⁵R¹⁶;    —(CH₂)_(q)C(═NOR¹⁷)NR¹⁵R¹⁶; —(CH₂)_(q)C(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CR¹R¹³)_(q)NR²C(═NR¹⁷)NR¹⁵R¹⁶; —(CR¹R¹³)_(q)N═C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)O(CH₂)_(m)NR¹⁵R¹⁶; —(CH₂)_(n)O(CH₂)_(m)C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)C(═NOR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)C(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)O(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)N═C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)S(CH₂)_(m)NR¹⁵R¹⁶; —(CH₂)_(n)S(CH₂)_(m)C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)S(CH₂)_(m)C(═NOR⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)S(CH₂)_(m)C(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)S(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶; or    —(CH₂)_(n)S(CH₂)_(m)N═C(NR¹⁵R¹⁶) NR¹⁷R¹⁸;

-   R^(Het) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R¹³)_(q)OR¹⁴; —(CR¹R¹³)_(q)SR¹⁵;    —(CR¹R¹³)_(q)SO₂R¹⁵; —(CR¹R¹³)_(q)SO₂NR¹R¹⁴;    —(CR¹R¹³)_(q)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(q)NR¹⁴SO₂R¹⁵;    —(CR¹R¹³)_(q)NR¹⁴SO₂NR¹⁵R¹⁶; —(CH₂)_(n)O(CH₂)_(m)OR¹⁴;    —(CH₂)_(n)O(CH₂)_(m)SR¹⁵; —(CR¹R¹³)_(q)COOR¹⁵;    —(CR¹R¹³)_(q)CONR¹⁵R¹⁶; —(CR¹R¹³)_(q)NR¹⁵R²⁷; or    —(CR¹R¹³)_(q)NR²CONR¹⁵R¹⁶;

-   R^(OH) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R¹³)_(q)OH; —(CR¹R¹³)_(q)SH;    —(CH₂)_(n)O(CH₂)_(m)OH; —(CH₂)_(n)S(CH₂)_(m)OH;    —(CH₂)_(n)NR¹(CH₂)_(m)OH; hydroxy-C₁₋₈-alkyl; hydroxy-C₂₋₈-alkenyl;    hydroxy-cycloalkyl; or hydroxy-heterocycloalkyl;

-   Z is, with the proviso of containing less than 25 carbon- and/or    heteroatoms, —(CH₂)_(n)—S—S—(CH₂)_(m)—;    —(CR²⁸R²⁹)_(n)—S—S—(CR²⁸R²⁹)_(m)—; —(CH₂)_(n)CH═CH(CH₂)_(m)—;    —(CR²⁸R²⁹)_(n)CH═CH(CR²⁸R²⁹)_(m)—; —(CH₂)_(n)-heteroaryl-(CH₂)_(m)—;    —(CR²⁸R²⁹)_(n)-heteroaryl-(CR²⁸R²⁹)_(m)—; —(CH₂)_(n)CONR¹(CH₂)_(m)—;    —(CH₂)_(n)NR¹CO(CH₂)_(m)—(CR²⁸R²⁹)_(n)CONR¹(CR²⁸R²⁹)_(m)—;    —(CR²⁸R²⁹)_(n)NR¹CO(CR²⁸R²⁹)_(m)—; —(CH₂)_(n)NR¹CONR²(CH₂)_(m)—; or    —(CR²⁸R²⁹)_(n)NR¹CONR²(CR²⁸R²⁹)_(m)—;

-   R¹, R² and R³ are independently    -   H; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; or aryl-C₁₋₆alkyl;

-   R⁴, R⁵, R⁶, R⁷ and R⁸ are independently    -   H; F; CF₃; C₁₋₈alkyl; C₂₋₈-alkenyl; cycloalkyl;        heterocycloalkyl; aryl; heteroaryl;    -   aryl-C₁₋₆alkyl; heteroaryl-C₁₋₆-alkyl; —(CHR¹³)_(o)OR¹⁵;        —O(CO)R¹⁵; —(CHR¹³)_(o)SR¹⁵;    -   —(CHR¹³)_(o)NR¹⁵R¹⁶; —(CHR¹³)_(o)OCONR¹⁵R¹⁶;        —(CHR¹³)_(o)NR¹CONR¹⁵R¹⁶;    -   —(CHR¹³)_(o)NR¹COR¹⁵; —(CHR¹³)_(o)COOR¹⁵; —(CHR¹³)_(o)CONR¹⁵R¹⁶;        —(CHR¹³)_(o)PO(OR¹)₂;    -   —(CHR¹³)_(o)SO₂R¹⁵; —(CHR¹³)_(o)NR¹SO₂R¹⁵;        —(CHR¹³)_(o)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(o)R²³; or    -   —(CHR¹)_(n)O(CHR²)_(m)R²³; or

-   R⁴ and R²; or R⁵ and R⁶ taken together can form:    -   ═O; ═NR¹; ═NOR¹; ═NOCF₃; or —(CHR¹)_(p)—;

-   R⁴ and R⁵; R⁶ and R⁷; R⁷ and R⁸; or R⁶ and R⁹ taken together can    form:    -   —(CHR¹)_(p)—; —(CH₂)_(n)O(CH₂)_(m)—; —(CH₂)_(n)S(CH₂)_(m)—; or        —(CH₂)_(n)NR¹(CH₂)_(m)—;

-   R⁹ is H; F; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl; aryl; heteroaryl;    -   aryl-C₁₋₆alkyl; heteroaryl-C₁₋₆-alkyl; —(CHR¹³)_(r)OR¹⁵; —O(CO)        R¹⁵; —(CHR¹³)_(r)SR¹⁵;    -   —(CHR¹⁰)_(r)NR¹⁵R¹⁶; —(CHR¹³)_(r)OCONR¹⁵R¹⁶;        —(CHR¹³)_(r)NR¹CONR¹⁵R¹⁶;    -   —(CHR¹³)_(r)NR¹COR¹⁵; —(CHR¹³)_(o)COOR¹⁵; —(CHR¹³)_(o)CONR¹⁵R¹⁶;        —(CHR¹³)_(r)PO(OR¹)₂;    -   —(CHR¹³)_(r)SO₂R¹⁵; —(CHR¹³)_(r)NR¹SO₂R¹⁵;        —(CHR¹³)_(r)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(o)R²³; or    -   —(CH R)_(r)O(CH R)_(o)R²³;

-   R¹⁰, R¹¹ and R¹² are independently    -   H; F; Cl; Br; I; CF₃; OCF₃; OCHF₂; CN; NO₂; C₁₋₈-alkyl;        C₂₋₈-alkenyl; aryl; heteroaryl;    -   aryl-C₁₋₆-alkyl; heteroaryl-C₁₋₆-alkyl; —(CHR¹³)_(o)OR¹⁵;        —O(CO)R¹⁵;    -   —(CHR¹³)_(o)SR¹⁵;    -   —(CHR¹³)_(o)NR¹⁵R¹⁶; —(CHR¹³)_(o)OCONR¹⁵R¹⁶;        —(CHR¹³)_(o)NR¹CONR¹⁵R¹⁶;    -   —(CHR¹³)_(o)NR¹COR¹⁵; —(CHR¹³)_(o)COOR¹⁵; —(CHR¹³)_(o)CONR¹⁵R¹⁶;        —(CHR¹³)_(o)PO(OR¹)₂;    -   —(CHR¹³)_(o)SO₂R¹⁵; —(CHR¹³)_(o)NR¹SO₂R¹⁵;        —(CHR¹³)_(o)SO₂NR¹⁵R¹⁶; or —(CR¹R¹³)_(o)R²³;

-   R¹³ is H; F; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl;    -   cycloalkyl-C₁₋₆-alkyl; heterocycloalkyl-C₁₋₆-alkyl; aryl;        heteroaryl;    -   aryl-C₁₋₆-alkyl; heteroaryl-C₁-alkyl; —(CHR¹)_(o)OR¹⁵; —OCOR¹;        —(CHR¹)_(o)NR¹⁵R¹⁶;    -   —COOR¹⁵; —CONR¹⁵R¹⁶; —SO₂R¹⁵; or —SO₂NR¹⁵R¹⁶;

-   R¹⁴ is H; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl;    -   cycloalkyl-C₁₋₆-alkyl; heterocycloalkyl-C₁₋₆-alkyl; aryl;        heteroaryl;    -   aryl-C₁₋₆-alkyl; heteroaryl-C₁₋₆-alkyl; cycloalkyl-aryl;        heterocycloalkyl-aryl;    -   cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl;        aryl-cycloalkyl;    -   aryl-heterocycloalkyl; heteroaryl-cycloalkyl;        heteroaryl-heterocycloalkyl;    -   —(CHR¹)_(o)OR¹⁵; —(CH R)_(o)SR¹⁵; —(CH R)_(o)NR¹⁵R¹⁶; —(CH        R)_(o)COOR¹⁵;    -   —(CHR¹)_(o)CONR¹⁵R¹⁶; or —(CHR¹)_(o)SO₂R¹⁵;

-   R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are independently    -   H; C₁₋₈-alkyl; C₂₋₈-alkenyl; C₁₋₆-alkoxy; cycloalkyl;        heterocycloalkyl;    -   cycloalkyl-C₁₋₆-alkyl; heterocycloalkyl-C₁₋₆-alkyl; aryl;        heteroaryl;    -   aryl-C₁₋₆-alkyl; heteroaryl-C₁₋₆-alkyl; cycloalkyl-aryl;        heterocycloalkyl-aryl;    -   cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl;        aryl-cycloalkyl;    -   aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or        heteroaryl-heterocycloalkyl;    -   or the structural elements —NR¹⁵R¹⁶ and —NR¹⁷R¹⁸ can        independently form:    -   heterocycloalkyl; aryl-heterocycloalkyl; or        heteroaryl-heterocycloalkyl;

-   R¹⁹ is an aryl group of one of the formulae

-   -   or a group of one of the formulae

-   X, X′, X″ and X′″ are independently    -   —CR²⁰; or N;-   R²⁰ and R²¹ are independently    -   H; F; Cl; Br; I; OH; NH₂; NO₂; CN; CF₃; OCHF₂; OCF₃; C₁₋₈-alkyl;        C₂₋₈-alkenyl; aryl;    -   heteroaryl; aryl-C₁₋₆-alkyl; heteroaryl-C₁₋₆-alkyl;        —(CH₂)_(o)R²²; —(CH₂)_(o)OR¹⁵; —O(CO)R¹⁵;    -   —O(CH₂)_(o)R²²; —(CH₂)_(o)SR¹⁵; —(CH₂)_(o)NR¹⁵R¹⁶;        —(CH₂)_(o)OCONR¹⁵R¹⁶;    -   —(CH₂)_(o)NR¹CONR¹⁵R¹⁶; —(CH₂)_(o)NR¹COR¹⁵; —(CH₂)_(o)COOR¹⁵;        —(CH₂)_(o)CONR¹⁵R¹⁶;    -   —(CH₂)_(o)PO(OR¹)₂; —(CH₂)_(o)SO₂R¹⁴; or —(CH₂)_(o)COR¹⁵;-   R²² is an aryl group of the formula

-   R²³, R²⁴ and R²⁵ are independently    -   H; F; Cl; Br; I; OH; NH₂; NO₂; CN; CF₃; OCHF₂; OCF₃; C₁₋₈-alkyl;        C₂₋₈-alkenyl;    -   —(CH₂)_(o)OR¹⁵; —O(CO)R¹⁵; —(CH₂)_(o)NR¹R¹⁵; —(CH₂)_(o)COOR¹⁵;        —(CH₂)_(o)CONR¹R¹⁵;-   R²⁶ is H; Ac; C₁₋₈-alkyl; or aryl-C₁₋₆-alkyl;-   R²⁷ is —CO(CR¹R¹³)_(q)R¹⁵;-   R²⁸ and R²⁹ are independently    -   H; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; or aryl-C₁₋₆-alkyl;        cycloalkyl-C₁₋₆-alkyl; or    -   heterocycloalkyl-C₁₋₆-alkyl;

n and m are independently an integer of 0-5 with the proviso that n+m≤6;

o is 0-4; p is 2-6; q is 1-6; and r is 1-3;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is an L α-amino acid residue of the formula AA8;    -   or an L α-amino acid residue of the formula AA10;

or

-   P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures of one    of the formulae AA13; or AA13^(D); with Z being, with the proviso of    containing less than 25 carbon- and/or heteroatoms,    —(CH₂)_(n)—S—S—(CH₂)_(m)—; —(CH₂)_(n)CONR¹(CH₂)_(m)—;    —(CH₂)_(n)NR¹CO(CH₂)_(m)—; or —(CH₂)_(n)NR¹CONR²(CH₂)_(m)—;-   or-   P² is an L α-amino acid residue of the formula AA8;    -   or an L α-amino acid residue of the formula AA10;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures of one of the formulae AA13; or AA13^(D); with        Z being, with the proviso of containing less than 25 carbon-        and/or heteroatoms, —(CH₂)_(n)—S—S—(CH₂)_(m)—;        —(CH₂)_(n)CONR¹(CH₂)_(m)—; —(CH₂)_(n)NR¹CO(CH₂)_(m)—; or        —(CH₂)_(n)NR¹CONR²(CH₂)_(m)—;

and

-   T¹ is an D α-amino acid residue of one of the formulae AA1^(D);    AA2^(D); AA3^(D); or AA12^(D);-   then T² is an L α-amino acid residue of the formula AA10 with R^(Am)    being, with the proviso of containing less than 26 carbon- and/or    heteroatoms, —(CR¹R¹³)_(q)NR²C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶; or    —(CH₂)_(n)S(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶;

and with the further proviso that

if no interstrand linkage is formed;

and

-   T¹ is an D α-amino acid residue of one of the formulae AA1^(D);    AA2^(D); or AA3^(D);

and

-   P² is Gly; or and L α-amino acid residue of AA7; AA9; or AA11;

then

-   T² is an L α-amino acid residue of AA7; AA8; or AA10.

Each single group “R^(x)” with the same index-number x for x=1-29 isindependently selected on each occurrence in a specific formula and,therefore, they can be the same or different.

As used in this description, the term “alkyl”, taken alone or incombinations (i.e. as part of another group, such as “aryl-C₁₋₆-alkyl”)designates saturated, straight-chain or branched hydrocarbon radicalsand may be optionally substituted. The term “C_(x-y)-alkyl” (x and yeach being an integer) refers to an alkyl group as defined beforecontaining x to y carbon atoms. For example a C₁₋₆-alkyl group containsone to six carbon atoms. Representative examples of alkyl groups includemethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl and the like.

The term “alkenyl”, taken alone or in combinations, designates straightchain or branched hydrocarbon radicals containing at least one or,depending on the chain length, up to four olefinic double bonds. Suchalkenyl moieties are optionally substituted and can independently existas E or Z configurations per double bond, which are all part of theinvention. The term “C_(x-y)-alkenyl” (x and y each being an integer)refers to an alkenyl group as defined before containing x to y carbonatoms.

The term “cycloalkyl”, taken alone or in combinations, refers to asaturated or partially unsaturated alicyclic moiety having from three toten carbon atoms and may be optionally substituted. Examples of thismoiety include, but are not limited to, cyclohexyl, norbornyl, decalinyland the like.

The term “heterocycloalkyl”, taken alone or in combinations, describes asaturated or partially unsaturated mono- or bicyclic moiety having fromthree to nine ring carbon atoms and one or more ring heteroatomsselected from nitrogen, oxygen or sulphur.

This term includes, for example, morpholino, piperazino, azetidinyl,pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl,1,7-diazaspiro[4.4]nonyl and the like. Said heterocycloalkyl ring(s)might be optionally substituted.

The term “aryl”, taken alone or in combinations, designates aromaticcarbocyclic hydrocarbon radicals containing one or two six-memberedrings, such as phenyl or naphthyl, which may be optionally substitutedby up to three substituents such as Br, Cl, F, CF₃, OH, OCF₃, OCHF₂,NH₂, N(CH₃)₂, NO₂, CN, C₁₋₆-alkyl, C₂₋₆-alkenyl, phenyl or phenoxy.

The term “heteroaryl”, taken alone or in combinations, designatesaromatic heterocyclic radicals containing one or two five- and/orsix-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and wherebythe heteroaryl radicals or tautomeric forms thereof may be attached viaany suitable atom. Said heteroaryl ring(s) are optionally substituted,e.g. as indicated above for “aryl”.

The term “aryl-C_(x-y)-alkyl”, as used herein, refers to anC_(x-y)-alkyl group as defined above, substituted by an aryl group, asdefined above. Representative examples of aryl-C_(x-y)-alkyl moietiesinclude, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl and the like.

The term “heteroaryl-C_(x-y)-alkyl”, as used herein, refers to anC_(x-y)-alkyl group as defined above, substituted by a heteroaryl group,as defined above. Examples of heteroaryl-C_(x-y)-alkyl groups includepyridin-3-ylmethyl, (1H-pyrrol-2-yl)ethyl and the like.

The term “aryl-cycloalkyl”, as used herein, refers to a cycloalkyl groupas defined above, substituted or annelated by an aryl group, as definedabove. Examples of aryl-cycloalkyl moieties include, but are not limitedto, phenylcyclopentyl, 2,3-dihydro-1H-indenyl,1,2,3,4-tetrahydronaphthalenyl and the like.

The term “aryl-heterocycloalkyl”, as used herein, refers to aheterocycloalkyl group as defined above, substituted or annelated by anaryl group, as defined above. Examples of aryl-heterocycloalkyl moietiesinclude, but are not limited to, indolinyl, 1,2,3,4-tetrahydroquinolinyland the like.

The term “heteroaryl-cycloalkyl”, as used herein, refers to a cycloalkylgroup as defined above, substituted or annelated by a heteroaryl group,as defined above. Examples of heteroaryl-cycloalkyl moieties include,but are not limited to, 5,6,7,8-tetrahydroquinolinyl and the like.

The term “heteroaryl-heterocycloalkyl”, as used herein, refers to aheterocycloalkyl group as defined above, substituted or annelated by aheteroaryl group, as defined above. Examples ofheteroaryl-heterocycloalkyl moieties include, but are not limited to,4-(thiazol-2-yl)piperazinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl andthe like.

The terms “cycloalkyl-aryl”, “heterocycloalkyl-aryl”,“cycloalkyl-heteroaryl”, and “heterocycloalkyl-heteroaryl”, as usedherein, are defined analogously to the terms “aryl-cycloalkyl”,“aryl-heterocycloalkyl”, “heteroaryl-cycloalkyl” and“heteroaryl-heterocycloalkyl”, as defined above, but connected in theopposite direction, e.g. instead of 4-(thiazol-2-yl)piperazinyl the termrefers to 2-(piperazin-1-yl)thiazolyl and the like.

The terms “hydroxy”, “alkoxy” and “aryloxy”, taken alone or incombinations, refer to the groups of —OH, —O-alkyl and —O-arylrespectively, wherein an alkyl group or an aryl group is as definedabove. The term “C_(x-y)-alkoxy” (x and y each being an integer) refersto an —O-alkyl group as defined before containing x to y carbon atomsattached to an oxygen atom. Representative examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxyand the like. Examples of aryloxy include e.g. phenoxy. For avoidance ofdoubt e.g. the term “hydroxy-C₁₋₈-alkyl” represents, among others,groups like e.g. hydroxymethyl, 1-hydroxypropyl, 2-hydroxypropyl or3-hydroxy-2,3-dimethylbutyl.

The term “optionally substituted” is in general intended to mean that agroup, such as, but not limited to C_(x-y)-alkyl, C_(x-y)-alkenyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C_(x-y)-alkoxy andaryloxy may be substituted with one or more substituents independentlyselected from amino (—NH₂), dimethylamino, nitro (—NO₂), halogen (F, Cl,Br, I), CF₃, cyano (—CN), hydroxy, methoxy, ethoxy, phenyloxy,benzyloxy, acetoxy, oxo (═O), carboxy, carboxamido, methyl, ethyl,phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate.

In the context of this invention the term “naturally or non-naturallyoccurring α-amino acid” typically comprises any natural α-amino acid,such as the proteogenic amino acids (examples listed below), theirnatural or semi-synthetic derivatives as well as α-amino acids of purelysynthetic origin. This term includes as well α-amino acids which areoptionally substituted at the α-nitrogen of the amino acid such as, butnot limited to, acetylation or alkylation, e.g. methylation, orbenzylation.

The term “aliphatic α-amino acid” refers to α-amino acids with analiphatic side-chain, such as, but not limited to, alanine, valine,leucine, isoleucine, n-octylglycine etc.

The term “aromatic α-amino acid” refer to α-amino acids with aside-chain comprising an aromatic or heteroaromatic group, such as, butnot limited to, phenylalanine, tryptophan, histidine, O-methyl-tyrosine,4-trifluormethyl-phenylalanine, 3,4-dichloro-homophenylalanine etc.

The term “basic α-amino acid” refers to α-amino acids with a side-chaincomprising at least one amino group, such as, but not limited to,lysine, ornithine etc. and further substituted derivatives thereof. Theaforesaid amino group can be substituted by amidino groups to formα-amino acids, such as, but not limited to, arginine, homoarginine etc.and further substituted derivatives thereof, or by diamino methylidinegroups.

The term “cross-linking α-amino acid” refers to α-amino acids with aside-chain comprising a function able to cross-link to a second α-aminoacid by a covalent bond, such as, but not limited to, cysteine,homocysteine etc.

The term “alcoholic α-amino acid” refers to α-amino acids with aside-chain comprising an alcoholic or thioalcoholic group, i.e. ahydroxy or sulfhydryl function, such as, but not limited to, serine,threonine etc.

For the avoidance of doubt the term “single side-chain” in the contextof an α-amino acid refers to a structure where the α-carbon of the aminoacid is covalently connected to the (in-chain) groups of the carbonyl(C═O) and nitrogen (N) as well as to one hydrogen (H) and one variableside-chain, e.g. as defined above. A “single side-chain” may include aswell a heterocyclic structure comprising the α-amino atom, such as butnot limited to, proline, pipecolic acid etc.

For the avoidance of doubt the term “heteroatom” refers to any atom thatis not carbon or hydrogen.

The descriptors L respectively D refer to the stereochemistry at theα-position of an α-amino acid and are used according theFischer-Rosanoff convention of the IUPAC.

The peptidomimetics of the present invention can also be diastereomers(e.g. epimers) of compounds of formula (I) if no specificstereochemistry of the chiral center is determined in the description.These stereoisomers can be prepared by a modification of the processdescribed below in which the appropriate isomers (e.g.epimers/enantiomers) of chiral starting materials are used. In case ofambiguous stereochemistry in the above description each single epimer ispart of the present invention as well as a mixture of both.

A further embodiment of the present invention may also includecompounds, which are identical to the compounds of formula (I), exceptthat one or more atoms are replaced by an atom having an atomic massnumber or mass different from the atomic mass number or mass usuallyfound in nature, e.g. compounds enriched in ²H (D), ³H, ¹¹C, ¹⁴C, ¹²⁷Ietc. These isotopic analogs and their pharmaceutical salts andformulations are considered useful agents in the therapy and/ordiagnostic, for example, but not limited to, where a fine-tuning of invivo half-life time could lead to an optimized dosage regimen.

A further particular embodiment of the invention relates to derivativesof general formula (I), wherein specifically

-   T¹ is the D α-amino acid residue AA1^(D); AA12^(D); AA7^(D);    AA8^(D); AA10^(D); AA11^(D); AA7a; or AA7b;-   T² is an L α-amino acid residue of one of the formulae AA1; AA7;    AA8; or AA10;

or a pharmaceutically acceptable salt thereof.

An alternative particular embodiment of the invention relates toderivatives of general formula (I), wherein specifically

-   P¹ is an L α-amino acid residue of one of the formulae AA7; or AA8;-   P² is an L α-amino acid residue of one of the formulae AA7; AA8;    AA10; or AA11;-   P⁵ is an L α-amino acid residue of one of the formulae AA10; or    AA11;-   P⁶ is Gly; or an D or L α-amino acid residue of formula AA10;-   P⁹ is an L α-amino acid residue of one of the formulae AA7; AA8;    AA10; or AA11;-   P¹¹ is an L α-amino acid residue of one of the formulae AA7; or AA9;    AA10; AA11;-   P¹² is an L α-amino acid residue of one of the formulae AA7; AA8;    AA10; or AA11;-   P² and P¹¹ taken together and/or P° and P⁹ taken together can form    interstrand linking bis(amino acid)-structures of one of the    formulae AA13; or AA13^(D) with Z being, with the proviso of    containing less than 25 carbon- and/or heteroatoms,    —(CR²⁸R²⁹)_(n)—S—S—(CR²⁸R²⁹)_(m);    —(CR²⁸R²⁹)_(n)-heteroaryl-(CR²⁸R²⁹)_(m);    —(CR²⁸R²⁹)_(n)CONR¹(CR²⁸R²)_(m)—; —(CR²⁸R²⁹)_(n)NR¹CO(CR²⁸R²⁹)_(m)—;    or —(CR²⁸R²⁹)_(n)NR¹CONR²(CR²⁸R²⁹)_(m)—;

or a pharmaceutically acceptable salt thereof.

In another particular embodiment of the invention the elements ofgeneral formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Tic; ^(D)Ala; ^(D)Abu; ^(D)Leu; ^(D)Val;    ^(D)Nva; ^(D)Ile; ^(D)Tyr; ^(D)Phe; ^(D)Trp; ^(D)Dab; ^(D)Dap;    ^(D)Orn; ^(D)Lys; ^(D)Arg; ^(D)Thr; ^(D)alloThr; ^(D)Ser; ^(D)Hse;    NMeAla; NMeGly; NMeAbu; NMeLeu; NMelle; or NMeVal;-   T² is Pro; Pic; Oic; Tic; Ala; Abu; Leu; lie; Val; Nva; NMeAla;    NMeAbu; NMeLeu; NMelle; NMeVal; Tyr; Phe; Trp; Arg; Dab; Dap; Orn;    or Lys;-   P¹ is Ala; Abu; Leu; lie; Val; Nva; Nle; Cpa; Cpg; Phe; Tyr; or Trp;-   P² is Gly; Tyr; Phe; Trp; Dab; Dap; Orn; Lys; Arg; Thr; alloThr;    Ser; Hse; Ala; Abu; Leu; lie; Val; Nva; Asn; Gin; Asp; or Glu;-   P³ is Val; tBuGly; Ala; Leu; Ile; Val; Nva; Tyr; Phe; or Trp;-   P⁴ is Ala; Val; Abu; Leu; lie; Nva; Dab; Dap; Orn; Lys; Arg; Asn;    Gin; Thr; alloThr; Ser; or Hse;-   P⁵ is Orn; Dap; Dab; Lys; Arg; Thr; alloThr; Ser; or Hse;-   P⁶ is Gly; Dab; ^(D)Dab; Dap; ^(D)Dap; Orn; ^(D)Orn; Lys; ^(D)Lys;    Arg; or ^(D)Arg;-   P⁷ is Dab; Dap; Orn; Lys; or Arg;-   P⁸ is Trp; Phe; Tyr; Phg; Leu; lie; Val; Nva; Abu; or Ala;-   P⁹ is Ala; Abu; Leu; Ile; Val; Nva; Tyr; Phe; Trp; Dab; Dap; Orn;    Lys; Arg; Ser; Thr; alloThr; or Hse;-   P¹⁰ is Val; tBuGly; Ala; Leu; Ile; Nva; Abu; Chg; Tyr; Phe; Trp; or    Phg;-   P¹¹ is Ala; Val; Abu; Nva; Leu; lie; Ser; Thr; alloThr; Hse; Asn;    Gin; Asp; Glu; Dab; Dap; Orn; Lys; or Arg;-   P¹² is Val; Ala; Abu; Nva; Leu; lie; Tyr; His; Phe; Trp; Dab; Dap;    Orn; Lys; Arg; Ser; Thr; alloThr; or Hse;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together can form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Tyr; Phe; Trp; Dab; Dap; Orn; Lys; or Arg;

or

-   P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

or

-   P² is Tyr; Phe; Trp; Dab; Dap; Orn; Lys; or Arg;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following connection of the side chain of Cys; or Hcy;        with the side chain of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

and

-   T¹ is ^(D)Pro; ^(D)Azt; or ^(D)Tic;-   then T² is Arg;

and with the further proviso that

if no interstrand linkage is formed;

and

-   T¹ is ^(D)Pro; or ^(D)Tic;

and

-   P² is Gly; Thr; alloThr; Ser; Hse; Ala; Abu; Leu; lie; Val; Nva;    Asn; Gln; Asp; or Glu;

then

-   T² is Ala; Abu; Leu; lie; Val; Nva; NMeAla; NMeAbu; NMeLeu; NMelle;    NMeVal; Tyr; Phe; Trp; Arg; Dab; Dap; Orn; or Lys.

In another particular embodiment of the invention the elements ofgeneral formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla;    or NMeGly;-   T² is Pro; Ala; Leu; NMeAla; Tyr; Phe; Dab; Dap; Orn; Lys; or Arg;-   P¹ is Leu; lie; Val; Cpa; Cpg; Phe; or Trp;-   P² is Tyr; Dab; Dap; Lys; Thr; Ser; Asp; or Glu;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Dab; Arg; Asn; or Thr;-   P⁵ is Orn; Dap; Dab; or Thr;-   P⁶ is Gly; Dab; or ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Dab; Dap; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; Phg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; Asp; Dap; Dab; or Lys;-   P¹² is Val; Tyr; His; Dab; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together can form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Tyr; Dab; Dap; or Lys;

or

-   P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

or

-   P² is Tyr; Dab; Dap; or Lys;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

and

-   T¹ is ^(D)Pro; or ^(D)Azt;-   then T² is Arg;

and with the further proviso that

if no interstrand linkage is formed;

and

-   T¹ is ^(D)Pro;

and

P² is Thr; Ser; Asp; or Glu;

then

-   T² is Ala; Leu; NMeAla; Tyr; Phe; Dab; Dap; Orn; Lys; or Arg.

In a further particular embodiment of the invention the elements ofgeneral formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla; or    NMeGly;-   T² is Pro; Ala; NMeAla Tyr; Arg; or Dab;-   P¹ is Leu; lie; Val; Cpa; Cpg; or Phe;-   P² is Tyr; Dab; Dap; Thr; or Ser;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Dab; Asn; or Thr;-   P⁵ is Orn; Dap; or Dab;-   P⁶ is Dab; ^(D)Dab; or Gly;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Dab; Dap; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; or Asp;-   P¹² is Val; Tyr; Dab; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together can form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Pen; with the side chain        of Cys; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Tyr; Dab; or Dap;

or

-   P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys with the side chain of Cys        by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage;

or

-   P² is Tyr; Dab; or Dap;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following connection of the side chain of Cys with the        side chain of Cys by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage;

and

-   T¹ is ^(D)Pro;-   then T² is Arg;

and with the further proviso that

if no interstrand linkage is formed;

and

-   T¹ is ^(D)Pro;

and

-   P² is Thr; or Ser;

then

-   T² is Ala; NMeAla; Tyr; Dab; or Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Tic; ^(D)Ala; ^(D)Abu; ^(D)Leu; ^(D)Val;    ^(D)Nva; ^(D)Ile; ^(D)Tyr; ^(D)Phe; ^(D)Trp; ^(D)Dab; ^(D)Dap;    ^(D)Orn; ^(D)Lys; ^(D)Arg; ^(D)Thr; ^(D)alloThr; ^(D)Ser; ^(D)Hse;    NMeAla; NMeGly; NMeAbu; NMeLeu; NMelle; or NMeVal;-   T² is Pro; Pic; Oic; Tic; Ala; Abu; Leu; Ile; Val; Nva; NMeAla;    NMeAbu; NMeLeu; NMelle; NMeVal; Tyr; Phe; Trp; Arg; Dab; Dap; Orn;    or Lys;-   P¹ is Ala; Abu; Leu; lie; Val; Nva; Nle; Cpa; Cpg; Phe; Tyr; or Trp;-   P² is Gly; Tyr; Phe; Trp; Dab; Dap; Orn; Lys; Arg; Thr; alloThr;    Ser; Hse; Ala; Abu; Leu; lie; Val; Nva; Asn; Gln; Asp; or Glu;-   P³ is Val; tBuGly; Ala; Leu; Ile; Val; Nva; Tyr; Phe; or Trp;-   P⁴ is Ala; Val; Abu; Leu; Ile; Nva; Dab; Dap; Orn; Lys; Arg; Asn;    Gin; Thr; alloThr; Ser; or Hse;-   P⁵ is Orn; Dap; Dab; Lys; Arg; Thr; alloThr; Ser; or Hse;-   P⁶ is Gly; Dab; ^(D)Dab; Dap; ^(D)Dap; Orn; ^(D)Orn; Lys; ^(D)Lys;    Arg; or ^(D)Arg;-   P⁷ is Dab; Dap; Orn; Lys; or Arg;-   P⁸ is Trp; Phe; Tyr; Phg; Leu; lie; Val; Nva; Abu; or Ala;-   P⁹ is Ala; Abu; Leu; Ile; Val; Nva; Tyr; Phe; Trp; Dab; Dap; Orn;    Lys; Arg; Ser; Thr; alloThr; or Hse;-   P¹⁰ is Val; tBuGly; Ala; Leu; Ile; Nva; Abu; Chg; Tyr; Phe; Trp; or    Phg;-   P¹¹ is Ala; Val; Abu; Nva; Leu; Ile; Ser; Thr; alloThr; Hse; Asn;    Gin; Asp; Glu; Dab; Dap; Orn; Lys; or Arg;-   P¹² is Val; Ala; Abu; Nva; Leu; lie; Tyr; His; Phe; Trp; Dab; Dap;    Orn; Lys; Arg; Ser; Thr; alloThr; or Hse;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap;    -   Dab; or Orn; by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

or

-   P² is Tyr; Phe; Trp; Dab; Dap; Orn; Lys; or Arg;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following connection of the side chain of Cys; or Hcy;        with the side chain of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

and

-   T¹ is ^(D)Pro; ^(D)Azt; or ^(D)Tic;-   then T² is Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla;    or NMeGly;-   T² is Pro; Ala; Leu; NMeAla; Tyr; Phe; Dab; Dap; Orn; Lys; or Arg;-   P¹ is Leu; Ile; Val; Cpa; Cpg; Phe; or Trp;-   P² is Tyr; Dab; Dap; Lys; Thr; Ser; Asp; or Glu;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Dab; Arg; Asn; or Thr;-   P⁵ is Orn; Dap; Dab; or Thr;-   P⁶ is Gly; Dab; or ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Dab; Dap; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; Phg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; Asp; Dap; Dab; or Lys;-   P² is Val; Tyr; His; Dab; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

or

P² is Tyr; Dab; Dap; or Lys;

-   -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following connection of the side chain of Cys; or Hcy;        with the side chain of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

and

-   T¹ is ^(D)Pro; or ^(D)Azt;-   then T² is Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla; or    NMeGly;-   T² is Pro; Ala; Tyr; Arg; or Dab;-   P¹ is Leu; lie; Val; Cpa; Cpg; or Phe;-   P² is Tyr; Dab; Thr; or Ser;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Dab; Asn; or Thr;-   P⁵ is Orn; Dap; or Dab;-   P⁶ is Dab; ^(D)Dab; or Gly;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Dab; Dap; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; or Asp;-   P¹² is Val; Tyr; Dab; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Pen; with the side chain        of Cys; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys with the side chain of Cys        by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage;

or

P² is Tyr; or Dab;

-   -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following    -   connection of the side chain of Cys with the side chain of Cys        by a disulfide linkage; or    -   connection of the side chain of Dab with the side chain of Asp        by a lactam linkage;

and

-   T¹ is ^(D)Pro;-   then T² is Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Tic; ^(D)Ala; ^(D)Abu; ^(D)Leu; ^(D)Val;    ^(D)Nva; ^(D)Ile; ^(D)Tyr; ^(D)phe; ^(D)Trp; ^(D)Dab; ^(D)Dap;    ^(D)Orn; ^(D)Lys; ^(D)Arg; ^(D)Thr; ^(D)olloThr; ^(D)Ser; ^(D)Hse;    NMeAla; NMeGly; NMeAbu; NMeLeu; NMelle; or NMeVal;-   T² is Pro; Pic; Oic; Tic; Ala; Abu; Leu; lie; Val; Nva; NMeAla;    NMeAbu; NMeLeu; NMelle; NMeVal; Tyr; Phe; Trp; Arg; Dab; Dap; Orn;    or Lys;-   P¹ is Ala; Abu; Leu; lie; Val; Nva; Nle; Cpa; Cpg; Phe; Tyr; or Trp;-   P² is Gly; Tyr; Phe; Trp; Dab; Dap; Orn; Lys; Arg; Thr; alloThr;    Ser; Hse; Ala; Abu; Leu; lie; Val; Nva; Asn; Gin; Asp; or Glu;-   P³ is Val; tBuGly; Ala; Leu; lie; Val; Nva; Tyr; Phe; or Trp;-   P⁴ is Ala; Val; Abu; Leu; lie; Nva; Dab; Dap; Orn; Lys; Arg; Asn;    Gin; Thr; alloThr; Ser; or Hse;-   P⁵ is Orn; Dap; Dab; Lys; Arg; Thr; alloThr; Ser; or Hse;-   P⁶ is Gly; Dab; ^(D)Dab; Dap; ^(D)Dap; Orn; ^(D)Orn; Lys; ^(D)Lys;    Arg; or ^(D)Arg;-   P⁷ is Dab; Dap; Orn; Lys; or Arg;-   P⁸ is Trp; Phe; Tyr; Phg; Leu; lie; Val; Nva; Abu; or Ala;-   P⁹ is Ala; Abu; Leu; lie; Val; Nva; Tyr; Phe; Trp; Dab; Dap; Orn;    Lys; Arg; Ser; Thr; alloThr; or Hse;-   P¹⁰ is Val; tBuGly; Ala; Leu; lie; Nva; Abu; Chg; Tyr; Phe; Trp; or    Phg;-   P¹¹ is Ala; Val; Abu; Nva; Leu; lie; Ser; Thr; alloThr; Hse; Asn;    Gin; Asp; Glu; Dab; Dap; Orn; Lys; or Arg;-   P¹² is Val; Ala; Abu; Nva; Leu; lie; Tyr; His; Phe; Trp; Dab; Dap;    Orn; Lys; Arg; Ser; Thr; alloThr; or Hse;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Tyr; Phe; Trp; Dab; Dap; Orn; Lys; or Arg;

and

-   T¹ is ^(D)Pro; ^(D)Azt; or ^(D)Tic;

then

-   T² is Arg;

and with the further proviso that

-   if T¹ is ^(D)Pro; or ^(D)Tic;

and

-   P² is Gly; Thr; alloThr; Ser; Hse; Ala; Abu; Leu; lie; Val; Nva;    Asn; Gln; Asp; or Glu;

then

-   T² is Ala; Abu; Leu; lie; Val; Nva; NMeAla; NMeAbu; NMeLeu; NMelle;    NMeVal; Tyr; Phe; Trp; Arg; Dab; Dap; Orn; or Lys.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla;    or NMeGly;-   T² is Pro; Ala; Leu; NMeAla; Tyr; Phe; Dab; Dap; Orn; Lys; or Arg;-   P¹ is Leu; lie; Val; Nle; Phe; or Trp;-   P² is Tyr; Dab; Dap; Lys; Thr; Ser; Asp; or Glu;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Dab; Arg; Asn; or Thr;-   P⁵ is Orn; Dap; Dab; or Thr;-   P⁶ is Gly; Dab; or ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Dab; Dap; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; Phg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; Asp; Dap; Dab; or Lys;-   P¹² is Val; Tyr; His; Dab; Ser; or Thr;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Tyr; Dab; Dap; or Lys;

and

-   T¹ is ^(D)Pro; or ^(D)Azt;

then

-   T² is Arg;

and with the further proviso that

-   if T¹ is ^(D)Pro;

and

-   P² is Thr; Ser; Asp; or Glu;

then

-   T² is Ala; Leu; NMeAla; Tyr; Phe; Arg; Dab; Dap; Orn; or Lys.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Ala; or ^(D)Dab;-   T² is Pro; Tyr; or NMeAla;-   P¹ is lie; Val; or Phe;-   P² is Dap; Ser; or Thr;-   P³ is Tyr;-   P⁴ is Dab;-   P⁵ is Orn; Dap; or Dab;-   P⁶ is ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp;-   P⁹ is Dab;-   P¹⁰ is tBuGly;-   P¹¹ is Ala; or Ser;-   P¹² is Thr; or Ser;

or a pharmaceutically acceptable salt thereof;

with the proviso that

if no interstrand linkage is formed; and

-   -   P² is Dap;

and

-   T¹ is ^(D)Pro; or ^(D)Azt;

then

-   T² is Arg;

and with the further proviso that

-   if T¹ is ^(D)Pro;

and

-   P² is Ser; or Thr;

then

-   T² is NMeAla; or Tyr.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Tic; ^(D)Ala; ^(D)Abu; ^(D)Leu; ^(D)Val;    ^(D)Nva; ^(D)Ile; ^(D)Tyr; ^(D)Phe; ^(D)Trp; ^(D)Dab; ^(D)Dap;    ^(D)Orn; ^(D)Lys; ^(D)Arg; ^(D)Thr; ^(D)olloThr; ^(D)Ser; ^(D)Hse;    NMeAla; NMeGly; NMeAbu; NMeLeu; NMelle; or NMeVal;-   T² is Arg; Dab; Dap; Orn; or Lys;-   P¹ is Ala; Abu; Leu; lie; Val; Nva; Nle; Cpa; Cpg; Phe; Tyr; or Trp;-   P² is Gly; Tyr; Phe; Trp; Thr; alloThr; Ser; Hse; Ala; Abu; Leu;    lie; Val; Nva; Asn; Gln; Asp; or Glu;-   P³ is Val; tBuGly; Ala; Leu; lie; Val; Nva; Tyr; Phe; or Trp;-   P⁴ is Ala; Val; Abu; Leu; lie; Nva; Asn; Gln; Thr; alloThr; Ser; or    Hse;-   P⁵ is Orn; Dap; Dab; Lys; or Arg;-   P⁶ is Dab; ^(D)Dab; Dap; ^(D)Dap; Orn; ^(D)Orn; Lys; ^(D)Lys; Arg;    or ^(D)Arg;-   P⁷ is Dab; Dap; Orn; Lys; or Arg;-   P⁸ is Trp; Phe; Tyr; Phg; Leu; lie; Val; Nva; Abu; or Ala;-   P⁹ is Ala; Abu; Leu; lie; Val; Nva; Tyr; Phe; Trp; Ser; Thr;    alloThr; or Hse;-   P¹⁰ is Val; tBuGly; Ala; Leu; lie; Nva; Abu; Chg; Tyr; Phe; Trp; or    Phg;-   P¹¹ is Ala; Val; Abu; Nva; Leu; lie; Ser; Thr; alloThr; Hse; Asn;    Gin; Asp; or Glu;-   P¹² is Val; Ala; Abu; Nva; Leu; lie; Tyr; His; Phe; Trp; Ser; Thr;    alloThr; or Hse;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

or

-   P² is Tyr; Phe; or Trp;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; Orn; or Lys; with the        side chain of Asp; Glu; or hGlu; by a lactam linkage; or    -   connection of the side chain of Dap; Dab; or Orn; with the side        chain of Dap; Dab; or Orn; by an urea linkage;

and

-   T¹ is ^(D)Pro; ^(D)Azt; or ^(D)Tic;-   then T² is Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Azt; ^(D)Ala; ^(D)Tyr; ^(D)Dab; ^(D)Thr; NMeAla;    or NMeGly;-   T² is Dab; Dap; Orn; Lys; or Arg;-   P¹ is Leu; Ile; Val; Cpa; Cpg; Phe; or Trp;-   P² is Tyr; Thr; Ser; Asp; or Glu;-   P³ is Val; tBuGly; or Tyr;-   P⁴ is Ala; Val; Asn; or Thr;-   P⁵ is Orn; Dap; or Dab;-   P⁶ is Dab; or ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Tyr; Ser; or Thr;-   P¹⁰ is Val; tBuGly; Chg; Phg; or Tyr;-   P¹¹ is Ala; Val; Ser; Thr; or Asp;-   P¹² is Val; Tyr; His; Dab; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; Hcy; or Pen; with the side        chain of Cys; Hcy; or Pen; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage; or    -   connection of the side chain of Pra with the side chain of        Abu(4N₃) by a 1,4-disubstituted 1,2,3-triazole-containing        linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together; or P² and P¹¹; and P⁴ and P⁹ taken    together; form interstrand linking bis(amino acid)-structures based    on the linkage of two L- or D-amino acid residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

or

-   P² is Tyr;    -   and P⁴ and P⁹ taken together form interstrand linking bis(amino        acid)-structures based on the linkage of two L- or D-amino acid        residues following    -   connection of the side chain of Cys; or Hcy; with the side chain        of Cys; or Hcy; by a disulfide linkage; or    -   connection of the side chain of Dap; Dab; or Lys; with the side        chain of Asp; or Glu; by a lactam linkage; or    -   connection of the side chain of Dap; with the side chain of Dap;        by an urea linkage;

and

-   T¹ is ^(D)Pro; or ^(D)Azt;-   then T² is Arg.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; or ^(D)Dab;-   T² is Arg; or Dab;-   P¹ is Leu; Cpa; Cpg; or lie;-   P² is Thr; or Ser;-   P³ is Val; or Tyr;-   P⁴ is Ala; Val; Asn; or Thr;-   P⁵ is Orn; or Dab;-   P⁶ is Dab; or ^(D)Dab;-   P⁷ is Dab;-   P⁸ is Trp; Phe; or Leu;-   P⁹ is Ala; Ser; Thr; or Tyr;-   P¹⁰ is Val; tBuGly; or Tyr;-   P¹¹ is Ala; Ser; or Thr;-   P¹² is Val; Tyr; Ser; or Thr;-   P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys; with the side chain of Cys;        by a disulfide linkage;

or a pharmaceutically acceptable salt thereof;

with the proviso that

-   if P² and P¹¹ taken together and/or P⁴ and P⁹ taken together form    interstrand linking bis(amino acid)-structures based on the linkage    of two L- or D-amino acid residues following    -   connection of the side chain of Cys with the side chain of Cys;        by a disulfide linkage;

and

-   T¹ is ^(D)Pro;-   then T² is Arg.

Hereinafter follows a list of abbreviations, corresponding to generallyadopted usual practice, of amino acids which, or the residues of which,are suitable for the purposes of the present invention and referred toin this document.

In spite of this specific determination of amino acids, it is notedthat, for a person skilled in the art, it is obvious that derivatives ofthese amino acids, resembling alike structural and physico-chemicalproperties, lead to functional analogs with similar biological activity,and therefore still form part of the gist of this invention.

-   Ala L-Alanine-   Arg L-Arginine-   Asn L-Asparagine-   Asp L-Aspartic acid-   Cit L-Citrulline-   Cys L-Cysteine-   Gin L-Glutamine-   Glu L-Glutamic acid-   Gly Glycine-   His L-Histidine-   lie L-Isoleucine-   Leu L-Leucine-   Lys L-Lysine-   Met L-Methionine-   Orn L-Ornithine-   Phe L-Phenylalanine-   Pro L-Proline-   Ser L-Serine-   Thr L-Threonine-   Trp L-Tryptophan-   Tyr L-Tyrosine-   Val L-Valine-   Abu (S)-2-aminobutanoic acid-   Abu(4N₃) (S)-2-amino-4-azidobutanoic acid-   Agp (S)-2-amino-3-guanidinopropanoic acid-   Ala(tBu) (S)-2-amino-4,4-dimethylpentanoic acid-   Ala(4butoxyPhUr) (S)-2-amino-3-(3-(4-butoxyphenyl)ureido)propanoic    acid-   Ala(cHex) (S)-2-amino-3-cyclohexylpropanoic acid-   Ala(cPr) (S)-2-amino-3-cyclopropylpropanoic acid-   Ala(iPrUr) (S)-2-amino-3-(3-isopropylureido) propa noic acid-   Ala(2ClPhUr) (S)-2-amino-3-(3-(2-chlorophenyl)ureido)propanoic acid-   Ala(4ClPhUr) (S)-2-amino-3-(3-(4-chlorophenyl)ureido)propanoic acid-   Ala(2Furyl) (S)-2-amino-3-(furan-2-yl)propanoic acid-   Ala(3Furyl) (S)-2-amino-3-(furan-3-yl)propanoic acid-   Ala(1Im) (S)-2-amino-3-(1H-imidazol-1-yl)propanoic acid-   Ala(2Im) (S)-2-amino-3-(1H-imidazol-2-yl)propanoic acid-   Ala(Ppz) (S)-2-amino-3-(piperazin-1-yl)propanoic acid-   Ala(cPr) (S)-2-amino-3-cyclopropylpropanoic acid-   Ala(Pyrazinyl) (S)-2-amino-3-(pyrazin-2-yl)propanoic acid-   Ala(1Pyrazolyl) (S)-2-amino-3-(1H-pyrazol-1-yl)propanoic acid-   Ala(3Pyrazolyl) (S)-2-amino-3-(1H-pyrazol-3-yl)propanoic acid-   Ala(2Pyrimidin) (S)-2-amino-3-(pyrimidin-2-yl)propanoic acid-   Ala(4Pyrimidin) (S)-2-amino-3-(pyrimidin-4-yl)propanoic acid-   Ala(5Pyrimidin) (S)-2-amino-3-(pyrimidin-5-yl)propanoic acid-   Ala(3PyrMeUr) (S)-2-amino-3-(3-(pyridin-3-ylmethyl)ureido)propanoic    acid-   Ala(2Quin) (S)-2-amino-3-(quinolin-2-yl)propanoic acid-   Ala(3Quin) (S)-2-amino-3-(quinolin-3-yl)propanoic acid-   Ala(4Quin) (S)-2-amino-3-(quinolin-4-yl)propanoic acid-   Alb (S)-2-amino-3-ureidopropanoic acid-   tBuGly (S)-2-amino-3,3-dimethylbutanoic acid-   Bbta (S)-2-amino-3-(1-benzothiophen-3-yl)propanoic acid-   Bip (S)-2-amino-3-(4-biphenylyl)propanoic acid-   Cha (S)-2-amino-3-cyclohexylpropanoic acid-   Chg (S)-2-amino-2-cyclohexylacetic acid-   Cpa (S)-2-amino-3-cyclopentylpropanoic acid-   Cpg (S)-2-amino-2-cyclopentylacetic acid-   Dab (S)-2,4-diaminobutanoic acid-   Dab(Ac) (S)-4-acetamido-2-aminobutanoic acid-   Dab(cPr) (S)-2-amino-4-(cyclopropylamino)butanoic acid-   Dab(iPr) (S)-2-amino-4-(isopropylamino)butanoic acid-   Dab(2PyrMe) (S)-2-amino-4-(pyridin-2-ylmethylamino)butanoic acid-   Dap (S)-2,3-diaminopropanoic acid-   Dap(Ac) (S)-3-acetamido-2-aminopropanoic acid-   Dap(AcThr)    (S)-3-((2S,3R)-2-acetamido-3-hydroxybutanamido)-2-aminopropanoic-   acid-   Dap(cPr) (S)-2-amino-3-(cyclopropylamino)propa noic acid-   Dap(iPr) (S)-2-amino-3-(isopropylamino)propanoic acid-   Dap(MeSO₂) (S)-2-amino-3-(methylsulfonamido)propanoic acid-   Dap(2,3-OHpropionyl) (2S)-2-amino-3-(2,3-dihydroxypropanamido)propa    noic acid-   Dap(Thr)    (S)-2-amino-3-((2S,3R)-2-amino-3-hydroxybutanamido)-propanoic-   acid-   Gly(cPr) (S)-2-amino-2-cyclopropylacetic acid-   hAla(1Im) (S)-2-amino-3-(1H-imidazol-1-yl)-butanoic acid-   hAla(2Im) (S)-2-amino-3-(1H-imidazol-2-yl)-butanoic acid-   hArg (S)-2-amino-6-guanidinohexanoic acid-   hCha (S)-2-amino-4-cyclohexylbuta noic acid-   hCys, hCy (S)-2-amino-4-mercaptobutanoic acid-   hHis (S)-2-amino-4-(1H-imidazol-5-yl)butanoic acid-   hLeu (S)-2-amino-5-methylhexa noic acid-   hLys (S)-2,7-diaminoheptanoic acid-   h2Pal (S)-2-amino-4-(pyridin-2-yl)-butanoic acid-   h3Pal (S)-2-amino-4-(pyridine-3-yl)-buta noic acid-   h4Pal (S)-2-amino-4-(pyridine-4-yl)-buta noic acid-   hSer, Hse (S)-2-amino-4-hydroxybutanoic acid-   hTrp (S)-2-amino-4-(1H-indol-3-yl)butanoic acid-   hTyr (S)-2-amino-4-(4-hydroxyphenyl)buta noic acid-   His(Me) (S)-2-amino-3-(1-methyl-1H-imidazol-5-yl)propa noic acid-   His(Bn) (S)-2-amino-3-(1-benzyl-1H-imidazol-5-yl)propanoic acid-   Lys(Bz) (S)-2-amino-6-benzamidohexanoic acid-   Lys(Me) (S)-2-amino-6-(methylamino)hexanoic acid-   Lys(Nic) (S)-2-amino-6-(nicotinamido)hexanoic acid-   Met(O₂) (S)-2-amino-4-(methylsulfonyl)butanoic acid-   1Nal (S)-2-amino-3-naphthalen-1-ylpropanoic acid-   2Nal (S)-2-amino-3-naphthalen-2-ylpropanoic acid-   Nle (S)-2-amino-hexanoic acid-   Nle(6OBn) (S)-2-amino-6-(benzyloxy) hexanoic acid-   NMeGly N-Methylglycine-   NMeAla L-N-Methylalanine-   NMeAbu N-Methyl-(S)-2-aminobutanoic acid-   NMeVal L-N-Methylvaline-   NMeLeu L-N-Methylleucine-   NMelle L-N-Methylisoleucine-   Nva (S)-2-aminopentanoic acid-   OctG (S)-2-aminodecanoic acid-   Oic (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid-   Orn(Ac) (S)-5-acetamido-2-aminopentanoic acid-   Orn(cPr) (S)-2-amino-5-(cyclopropylamino)pentanoic acid-   Orn(iPr) (S)-2-amino-5-(isopropylamino)pentanoic acid-   2Pal (S)-2-amino-3-(pyridine-2-yl) propionic acid-   3Pal (S)-2-amino-3-(pyridine-3-yl)propionic acid-   4Pal (S)-2-amino-3-(pyridine-4-yl)propionic acid-   Pen (S)-2-amino-3-methyl-3-sulfanyl-butanoic acid-   Phe(2Cl) (S)-2-amino-3-(2-chlorophenyl)propanoic acid-   Phe(3Cl) (S)-2-amino-3-(3-chlorophenyl)propanoic acid-   Phe(4Cl) (S)-2-amino-3-(4-chlorophenyl)propa noic acid-   Phe(3,4Cl₂) (S)-2-amino-3-(3,4-dichlorophenyl)propanoic acid-   Phe(2F) (S)-2-amino-3-(2-fluorophenyl)propanoic acid-   Phe(3F) (S)-2-amino-3-(3-fluorophenyl)propanoic acid-   Phe(4F) (S)-2-amino-3-(4-fluorophenyl)propanoic acid-   Phe(3,4F₂) (S)-2-amino-3-(3,4-difluorophenyl)propanoic acid-   Phe(3CN) (S)-2-amino-3-(3-cyanophenyl)propanoic acid-   Phe(4CN) (S)-2-amino-3-(4-cyanophenyl)propanoic acid-   Phe(2CF₃) (S)-2-amino-3-(2-(trifluoromethyl)phenyl)propanoic acid-   Phe(3CF₃) (S)-2-amino-3-(3-(trifluoromethyl)phenyl)propanoic acid-   Phe(4CF₃) (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoic acid-   Phe(3,4(CF₃)₂)    (S)-2-amino-3-(3,4-bis(trifluoromethyl)phenyl)propanoic acid-   Phe(4COOMe) (S)-2-amino-3-(4-(methoxycarbonyl)phenyl)propanoic acid-   Phe(4NH₂) (S)-2-amino-3-(4-aminophenyl)propanoic acid-   Phe(3OH) (S)-2-amino-3-(3-hydroxyphenyl)propanoic acid-   Phg (S)-2-amino-2-phenylacetic acid-   Pic (S)-piperidine-2-carboxylic acid-   Pip 4-aminopiperidine-4-carboxylic acid-   Pra L-propargylglycine-   Pro((4R)NH₂) (2S,4R)-4-aminopyrrolidine-2-carboxylic acid-   Pro((4S)NH₂) (2S,4S)-4-aminopyrrolidine-2-carboxylic acid-   Pro((3R)OH) (2S,3R)-3-hydroxypyrrolidine-2-carboxylic acid-   Pro((3S)OH) (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid-   Pro((4R)OH) (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid-   Pro((4S)OH) (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid-   Pro((4R)OBn) (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid-   Pro((4S)OBn) (2S,4S)-4-(benzyloxy)pyrrolidine-2-carboxylic acid-   Sar; NMeGly N-Methylglycine-   Ser(Bn) (S)-2-amino-3-(benzyloxy)propanoic acid-   Ser(Me) (S)-2-amino-3-methoxy-propanoic acid-   Thi (S)-2-amino-3-(thiophen-2-yl)propanoic acid-   alloThr (2S,3S)-2-amino-3-hydroxybuta noic acid-   Thr(Bn) (2S,3R)-2-amino-3-(benzyloxy)butanoic acid-   Thr(Me) (2S,3R)-2-amino-3-(methyloxy)butanoic acid-   Thz (R)-thiazolidine-4-carboxylic acid-   Thz(5,5Me₂) (R)-2,2-dimethylthiazolidine-4-carboxylic acid-   Tic (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid-   Tic(7OH) (S)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic    acid-   Trp(7Aza) (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic    acid-   Trp(5Br) (S)-2-amino-3-(5-bromo-1H-indol-3-yl)propa noic acid-   Trp(6Br) (S)-2-amino-3-(6-bromo-1H-indol-3-yl) propa noic acid-   Trp(6CF₃) (S)-2-amino-3-(6-(trifluoromethyl)-1H-indol-3-yl)propanoic    acid-   Trp(5Cl) (S)-2-amino-3-(5-chloro-1H-indol-3-yl)propanoic acid-   Trp(6Cl) (S)-2-amino-3-(6-chloro-1H-indol-3-yl)propanoic acid-   Trp(5,6Cl) (S)-2-amino-3-(5,6-dichloro-1H-indol-3-yl)propa noic acid-   Trp(50H) (S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid-   Tyr(Bn) (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid-   Tyr(Me) (S)-2-amino-3-(4-methoxyphenyl)propa noic acid-   Tyr(Ph) (S)-2-amino-3-(4-phenoxyphenyl)propanoic acid-   Tyr(4OHPh) (S)-2-amino-3-[4-(4-hydroxyphenoxy)phenyl]propanoic acid-   Tyr(3F) (S)-2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid-   Tza (S)-2-amino-3-(thiazol-4-yl)propa noic acid

The abbreviation of D-isomers, e.g. ^(D)Lys corresponds to the epimer atthe 2-position of the appropriate amino acid described above. Sameapplies for the generic descriptions of the amino acids, e.g. AA1 whichhas AA1^(D) as the corresponding α-epimer.

In a preferred embodiment of the invention the p-hairpin peptidomimeticsare selected from a group consisting of β-hairpin peptidomimetics ofgeneral formula (I) having a disulfide linkage; a lactam linkage; or a1,2,3-triazole linkage between P² and P¹¹.

cyclo(-Leu-Cys-Tyr-Ala-Dab-Dab-Dab-Trp-Ala-Val- Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Dab-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-tBuGly-Cys-Val-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-Val-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ser-^(D)Dab-Dab-); cyclo(-Val-Cys-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-NMeAla-Pro-;cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Ala-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Pro-);cyclo(-Val-Cys-Tyr-Dab-Dap-Dab-Dab-Trp-Dab-tBuGly-Cys-Thr-^(D)Tyr-Pro-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Ala-Tyr-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Phe-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Phe-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Dab-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Ser-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Dab-); cyclo(-Leu-Cys-Tyr-Asn-Orn-Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Dab-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpa-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpg-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Nva-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Abu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Gln-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-tBuGly-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Lys-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Arg-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Lys-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dap-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ala-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dap-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Ala-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Ala-Arg-); cyclo(-Leu-Pen-tBuGly-Dab-Orn-DDab-Dab-Trp-Dab-Chg-Pen-Ser-^(D)Pro-Pro-); cyclo(-Leu-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-Val-Asp-Thr-^(D)Ala-Pro-); cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Thr-^(D)Thr-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Ala-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dap-tBuGly-Asp-Ser-^(D)Ala-Tyr-);cyclo(-Val-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab- tBuGly-Asp-Ser-Sar-Pro-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Arg-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Dab-);cyclo(-Leu-Asp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Dab-Ser-^(D)Ala-Pro-); cyclo(-Val-Pra-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Abu(4N₃)-Ser-^(D)Pro-Pro-);

or a pharmaceutically acceptable salt thereof;

and/or

a group consisting of β-hairpin peptidomimetics of general formula (I)having a disulfide linkage; or a lactam linkage between P⁴ and P⁹; ordisulfide linkages between P² and P¹¹, and P⁴ and P⁹:

cyclo(-Leu-Thr-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Val- Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Trp-Cys-Tyr-Ala-Ser-^(D)Dab-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Phe-Cys-Val-Ser-Val-^(D)Dab-Arg-); cyclo(-Leu-Ser-Tyr-Cys-Orn-Gly-Dab-Trp-Cys-Val-Ala-Val-^(D)Dab-Arg-); cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asp-tBuGly-Val-Ser-^(D)Dab-Pro-);cyclo(-Leu-Cys-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Tyr- Cys-Val-Pro-Arg-);cyclo(-Leu-Cys-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Tyr-Cys-Val-^(D)Pro-Arg-);

or a pharmaceutically acceptable salt thereof;

and/or

a group consisting of β-hairpin peptidomimetics of general formula (I)

cyclo(-Val-Ser-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-NMeAla-);cyclo(-Val-Dap-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Val-Dap-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Tyr-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Ala-Tyr-);cyclo(-Phe-Dap-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);

or a pharmaceutically acceptable salt thereof.

In another preferred embodiment of the invention the β-hairpinpeptidomimetics of general formula (I) having a disulfide linkagebetween P² and P¹¹ and/or between P⁴ and P⁹ are selected from the groupconsisting of:

cyclo(-Leu-Cys-Tyr-Ala-Dab-Dab-Dab-Trp-Ala-Val- Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Dab-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-tBuGly-Cys-Val-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-Val-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ser-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Phe-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Val-^(D)Dab-Arg-); cyclo(-Leu-Thr-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Trp-Cys-Tyr-Ala-Ser-^(D)Dab-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Phe-Cys-Val-Ser-Val-^(D)Dab-Arg-); cyclo(-Leu-Ser-Tyr-Cys-Orn-Gly-Dab-Trp-Cys-Val-Ala-Val-^(D)Dab-Arg-); cyclo(-Leu-Cys-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Tyr-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Tyr-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Ser-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Dab-); cyclo(-Leu-Cys-Tyr-Asn-Orn-Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Dab-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpa-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpg-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Nva-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Abu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Gln-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-tBuGly-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Lys-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Arg-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Lys-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dap-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ala-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Arg-);

or a pharmaceutically acceptable salt thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

-   a) coupling an appropriately functionalized solid support with an    appropriately N-protected derivative of that amino acid which in the    desired end-product is in position T¹ or T² or P¹ to P¹² as defined    above; any functional group which may be present in said N-protected    amino acid derivative being likewise appropriately protected;-   (b) removing the N-protecting group from the product obtained in    step (a);-   (c) coupling the product thus obtained with an appropriately    N-protected derivative of that amino acid which in the desired    end-product is in the position of the next element (T or P),    following counterclockwise or clockwise the sequence according to    general formula (I) in —COOH to —NH2 orientation; any functional    group which may be present in said N-protected amino acid derivative    being likewise appropriately protected;-   (d) removing the N-protecting group from the product thus obtained;-   (e) repeating steps (c) and (d) until all amino acid residues have    been introduced;-   (f) if desired, selectively deprotecting one or several protected    functional group(s) present in the molecule and chemically    transforming the reactive group(s) thus liberated;-   (g) detaching the product thus obtained from the solid support;-   (h) cyclizing the product cleaved from the solid support;-   (i) if desired, selectively deprotecting one or several protected    functional group(s) present in the molecule and chemically    transforming the reactive group(s) thus liberated;-   (j) removing any protecting groups present on functional groups of    any members of the chain of amino acid residues and, if desired, any    protecting group(s) which may in addition be present in the    molecule;-   (k) if desired, implementing additional chemical transformations of    one or more reactive group(s) present in the molecule; and-   (l) if required, removing any protecting groups present on    functional groups of any members of the chain of amino acid residues    and, if desired, any protecting group(s) which may in addition be    present in the molecule;-   (m) if desired, converting the product thus obtained into a    pharmaceutically acceptable salt or converting a pharmaceutically    acceptable, or unacceptable, salt thus obtained into the    corresponding free compound of formula (I) or into a different,    pharmaceutically acceptable salt.

Enantiomers of the compounds defined herein before form also part of thepresent invention. These enantiomers can be prepared by a modificationof the above process wherein enantiomers of all chiral startingmaterials are utilized.

The process of the invention can advantageously be carried out asparallel array synthesis to yield libraries of β-hairpin peptidomimeticsof the invention. Such parallel syntheses allow one to obtain arrays ofnumerous (normally 12 to 576, typically 96) compounds as described abovein moderate to high yields and defined purities, minimizing theformation of dimeric and polymeric by-products. The proper choice of thefunctionalized solid-support (i.e. solid support plus linker molecule)and site of cyclization play thereby key roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel™); andpolyacrylamide resins (see also D. Obrecht, J.-M. Villalgordo,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidicconditions (H. Rink, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl) phenoxyacetamido)aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl]-4-methyl-benzydrylaminePS resin (Rink amide MBHA PS Resin), and 4-[(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] benzhydrylamine PS-resin(Rink amide BHA PS resin). Preferably, the support is derived frompolystyrene crosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 4-(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin™ linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array synthesis the process of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the invention.

A number of reaction vessels (normally 12 to 576, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 60 mg, of the appropriatefunctionalized solid support, preferably 1 to 5% cross-linkedpolystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (G. B. Fields, C. G. Fields, J. Am. Chem. Soc. 1991, 113,4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin™ linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008)is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) andis stable to Fmoc deprotection conditions during the peptide synthesis,Boc/tBu-based additional protecting groups being compatible with thisprotection scheme. Other linkers which are suitable for the process ofthe invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, H.Rink, Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Flörsheimer & Riniker, 1991, Peptides 1990: Proceedings ofthe Twenty-First European Peptide Symposium, 131) which is also cleavedwith 1% TFA/DCM in order to yield a peptide fragment containing all acidlabile side-chain protective groups; and, in addition, the2-chlorotritylchloride linker (Barlos et al., Tetrahedron Lett. 1989,30, 3943-3946), which allows the peptide detachment using a mixture ofglacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)    -   Cbz benzyloxycarbonyl    -   Boc tert.-butyloxycarbonyl    -   Fmoc 9-fluorenylmethoxycarbonyl    -   Alloc allyloxycarbonyl    -   Teoc trimethylsilylethoxycarbonyl    -   Tcc trichloroethoxycarbonyl    -   Nps o-nitrophenylsulfonyl    -   Trt triphenylmethyl or trityl    -   ivDe 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl;        -   for the carboxyl group (as is present e.g. also in the            side-chain of aspartic and glutamic acid) by conversion into            esters with the alcohol components    -   tBu tert.-butyl    -   Bn benzyl    -   Me methyl    -   Ph phenyl    -   Pac phenacyl allyl    -   Tse trimethylsilylethyl    -   Tce trichloroethyl    -   Dmab        4-N-(1-[dimethyl-2,6-dioxocyclohexylidene]-3-methylbutyl)-amino        benzyl;    -   for the guanidino group (as is present e.g. in the side-chain of        arginine)    -   Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl    -   Ts tosyl (i.e. p-toluenesulfonyl)    -   Cbz benzyloxycarbonyl    -   Pbf pentamethyldihydrobenzofuran-5-sulfonyl;    -   and for the hydroxy group (as is present e.g. in the side-chain        of threonine and serine)    -   tBu tert.-butyl    -   Bn benzyl    -   Trt trityl    -   Alloc allyloxycarbonyl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of theβ-hairpin loop mimetics of the invention. For the deprotection, i.e.cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2%piperidine in DMF can be used as well as 25% hexafluoroisopropanol inCH₂Cl₂.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents (eq) based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used, if required, todrive the reaction to completion in a reasonable time. The preferredworkstations (without, however, being limited thereto) are Labsource'sCombi-chem station, Protein Technologies' Symphony and MultiSynTech's-Syro synthesizer, the latter additionally equipped with atransfer unit and a reservoir box during the process of detachment ofthe fully protected linear peptide from the solid support. Allsynthesizers are able to provide a controlled environment, for example,reactions can be accomplished at temperatures different from roomtemperature as well as under inert gas atmosphere, if desired.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and,respectively, diisopropylurea is insoluble and, respectively, soluble inthe solvents generally used. In a variation of the carbodiimide method1-hydroxy benzotriazole (HOBt, König & Geiger, Chem. Ber. 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-(dimethyl-amino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino etal., Tetrahedron Lett. 1994, 35, 2279-2281) or-(6-Chloro-1H-benzotriazol-1-yl-)-N,N,N′,N′-1,1,3,3-tetramethyl uroniumtetrafluoroborate (TCTU), or hexafluoro phosphate (HCTU, Marder, Shivoand Albericio: HCTU and TCTU: New Coupling Reagents: Development andIndustrial Applications, Poster Presentation, Gordon Conference February2002) have also been used as coupling reagents as well as1,1,3,3-bis(tetramethylene)chlorouronium hexafluorophosphate (PyCIU)especially for coupling of N-methylated amino acids (J. Coste, E.Frerot, P. Jouin, B. Castro, Tetrahedron Lett. 1991, 32, 1967) orpentafluorophenyl diphenyl-phosphinate (S. Chen, J. Xu, TetrahedronLett. 1991, 32, 6711).

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide or peptide indicates qualitatively the presence ofthe primary amine, can easily and quickly be performed after eachcoupling step. Fmoc chemistry allows the spectrophotometric detection ofthe Fmoc chromophore when it is released with the base (Meienhofer etal., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction vessel is washed freeof excess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s).

Washing procedures are repeated up to about 30 times (preferably about 5times), monitoring the efficiency of reagent, solvent, and by-productremoval by methods such as TLC, GC, LC-MS or inspection of the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such an amino protecting group which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced.

After detachment of the fully protected linear peptide from the solidsupport the individual solutions/extracts are then manipulated as neededto isolate the final compounds. Typical manipulations include, but arenot limited to, evaporation, concentration, liquid/liquid extraction,acidification, basification, neutralization or additional reactions insolution.

The solutions containing fully protected linear peptide derivativeswhich have been cleaved off from the solid support and neutralized witha base, are evaporated. Cyclization is then effected in solution usingsolvents such as DCM, DMF, dioxane, THF and the like. Various couplingreagents which were mentioned earlier as activators for the amide bondformation can be used for the cyclization. The duration of thecyclization is about 6-48 hours, preferably about 16 hours. The progressof the reaction is followed, e.g. by RP-HPLC (Reverse Phase HighPerformance Liquid Chromatography). Then the solvent is removed byevaporation, the fully protected cyclic peptide derivative is dissolvedin a solvent which is not miscible with water, such as DCM, and thesolution is extracted with water or a mixture of water-misciblesolvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA,2.5% H₂O, 2.5% TIS, or 87.5% TFA, 2.5% DODT, 5% thioanisol, 5% H₂O oranother combination of scavengers for effecting the cleavage ofprotecting groups. The cleavage reaction time is commonly 30 minutes to12 hours, preferably about 2.5 hours. The volatiles are evaporated todryness and the crude peptide is dissolved in 20% AcOH in water andextracted with isopropyl ether or other solvents which are suitabletherefore. The aqueous layer is collected and evaporated to dryness, andthe fully deprotected cyclic peptide is obtained. Alternatively thedeprotected cyclic peptide can be precipitated and washed using coldEt₂O.

For some compounds of the present invention according general formula(I) additional synthetic steps are required. These transformations canbe applied either on a fully protected or partially deprotected linearor cyclic peptide, attached to or already released from the solidsupport or on the final deprotected molecule.

Various methods are known to form interstrand linkages including thosedescribed by: J. P. Tam et al., Synthesis 1979, 955-957; J. M. Stewartet al., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,Rockford, Ill., 1984; A. K. Ahmed et al., J. Biol. Chem. 1975, 250,8477-8482; and M. W. Pennington et al., Peptides, pages 164-166, Giraltand Andreu, Eds., ESCOM Leiden, The Netherlands, 1990; C. E.Schafmeister et al., J. Am. Chem. Soc. 2000, 122, 5891. The most widelyknown linkage is the disulfide bridge formed by e.g. cysteines andhomo-cysteines positioned at opposite positions of the f-strand.

For instance, the formation of a disulfide bridge can be carried outafter assembly of the linear peptide on resin by employing, for example,on trityl protected cysteine amino acid residues, 10 eq of iodinesolution in DMF for 1.5 h and repetition of the oxidation step with afresh iodine solution for additional 3 h. Alternatively, disulfidebridge formation can be performed in solution after backbone cyclizationbut before deprotection of the peptide by employing, for example, ontrityl protected cysteine amino acid residues, 2 eq of an iodinesolution in a hexafluoroisopropanol/CH₂Cl₂-mixture for 1 h followed byaddition of 1M aqueous solution of ascorbic acid to quench the oxidationreaction. Another possibility to form disulfide bridges remains afterdeprotection of the backbone-cyclized peptide by, for example, theapplication of a mixture of DMSO and acetic acid solution, buffered with5% NaHCO₃ to pH 5-6 for 4 h, or in water after adjusting to pH 8 withammonium hydroxide solution by stirring for 24 h.

Another well established interstrand linkage is the lactam bridge formedby linking e.g. the amino group-bearing side chains of ornithine andlysine, respectively, with the carboxyl group-bearing side chains ofglutamic and aspartic acid residues located at opposite p-strandpositions by means of an amide bond formation. Preferred protectivegroups for the side chain amino-groups of ornithine and lysine areallyloxycarbonyl (alloc) and for the side chain carboxyl-groups ofaspartic and glutamic acid allylesters (allyl).

For instance, the formation of a lactam bridge can be carried out afterassembly of the linear peptide on resin by applying 0.2 eqtetrakis(triphenyl-phosphine)palladium(0) (10 mM) in dry CH₂Cl₂ and 10eq phenylsilane to selectively remove alloc- and allyl-protecting groupsfrom amino and carboxyl functional groups of the side chains of aminoacid residues to be linked. After repetition of the above procedure, thelactam bridge is formed by adding 4 eq of DIPEA in DMF and subsequentaddition of 2 eq HATU in DMF. By applying an appropriate orthogonalprotecting group strategy lactam bridges may also be formed in a laterstage of the synthesis, e.g. after deprotection of backbone cyclizedpeptides.

Interstrand linkages can also be established by linking side chain aminogroups of amino acid residues like e.g. L-1,3-diamino propionic acid andornithine located at opposite β-strand positions with reagents such asN,N-carbonylimidazole or di(N-succinimidyl)carbonate to form cyclicureas. Allyloxycarbonyl (alloc) as orthogonal protecting group for aminofunctions may be preferably used.

For instance, the formation of an urea bridge can be carried out insolution after backbone cyclization, but before full deprotection of thepeptide, by applying 30 eq phenylsilane as well as a solution of 0.2 eqtetrakis(triphenylphosphine)-palladium(0) in CH₂Cl₂. After removal ofthe alloc protecting groups and precipitation of the selectivelydeprotected peptide the urea bridge is formed by adding 6 eq DIPEAdissolved in CH₂Cl₂ and subsequent dropwise addition of 1.2 eq ofdi(N-succinimidyl)carbonate in CH₂Cl₂. Recently, a further type ofinterstrand linkages based on 1,4-disubstituted1,2,3-triazole-containing alkanediyl groups have been introduced. Thelinkage is obtained through a 1,3-dipolar cycloaddition between thew-yne group of the side chain of an amino acid residue like e.g.L-propargylglycine and the w-azido group of the side chain of an aminoacid residue like e.g. (S)-2-amino-4-azidobutanoic acid, both residueslocated at opposite α-strand positions.

For instance, the formation of such a triazole-containing bridge isperformed by stirring the purified fully deprotected backbone-cyclizedpeptide in a mixture of H₂O/tBuOH, 4.4 eq of CuSO₄xSH₂O and 6.6 eq ofascorbic acid for 12 h.

Depending on its purity, the final product as obtained following theprocedures above can be used directly for biological assays, or has tobe further purified, for example by preparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to convertthe fully deprotected cyclic product thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree or into a different, pharmaceutically acceptable, salt. Any ofthese operations can be carried out by methods well known in the art.

In general the building blocks for the peptidomimetics of the presentinvention can be synthesized according to the literature methods, whichare known to a person skilled in the art or are commercially available.All other corresponding amino acids have been described either asunprotected or as Boc- or Fmoc-protected racemates, (D)- or (L)-isomers.It will be appreciated that unprotected amino acid building blocks canbe easily transformed into the corresponding Fmoc-protected amino acidbuilding blocks required for the present invention by standardprotecting group manipulations. Reviews describing general methods forthe synthesis of α-amino acids include: R. Duthaler, Tetrahedron(Report) 1994, 349, 1540-1650; R. M. Williams, “Synthesis of opticallyactive α-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J.E. Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989. Anespecially useful method for the synthesis of optically active α-aminoacids relevant for this invention includes kinetic resolution usinghydrolytic enzymes (M. A. Verhovskaya, I. A. Yamskov, Russian Chem. Rev.1991, 60, 1163-1179; R. M. Williams, “Synthesis of optically activeα-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J. E.Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989, Chapter 7,p. 257-279). Kinetic resolution using hydrolytic enzymes involveshydrolysis of amides and nitriles by aminopeptidases or nitrilases,cleavage of N-acyl groups by acylases, and ester hydrolysis by lipasesor proteases. It is well documented that certain enzymes will leadspecifically to pure (L)-enantiomers whereas others yield thecorresponding (D)-enantiomers (e.g.: R. Duthaler, Tetrahedron Report1994, 349, 1540-1650; R. M. Williams, “Synthesis of optically activeα-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J. E.Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989).

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to inhibit the growth of or to killmicroorganisms leading to the desired therapeutic effect in man or, dueto their similar etiology, in other mammals. In particular they can beused to inhibit the growth of or to kill Gram-negative bacteria such asKlebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichiacoli.

They can be used for example as disinfectants or as preservatives formaterials such as foodstuffs, cosmetics, medicaments and othernutrient-containing materials.

The β-hairpin peptidomimetics of the invention can also be used to treator prevent diseases related to microbial infection in plants andanimals.

For use as disinfectants or preservatives the β-hairpin peptidomimeticscan be added to the desired material singly, as mixtures of severalβ-hairpin peptidomimetics or in combination with other antimicrobialagents.

The β-hairpin peptidomimetics of the invention can be used to treat orprevent infections or diseases related to such infections, particularlynosocomial infections caused by Gram-negative bacteria related todiseases such as ventilator-associated pneumonia (VAP),hospital-acquired pneumonia (HAP), healthcare-associated pneumonia(HCAP); catheter-related and non-catheter-related infections such asurinary tract infections (UTIs) or bloodstream infections (BSIs);infections related to respiratory diseases such as cystic fibrosis,emphysema, asthma or pneumonia; infections related to skin or softtissue diseases such as surgical wounds, traumatic wounds or burn;infections related to gastrointestinal diseases such as epidemicdiarrhea, necrotizing enterocolitis, typhlitis, gastroenteritis orpancreatitis; infections related to eye diseases such as keratitis andendophthalmitis; infections related to ear diseases such as otitis;infections related to CNS diseases such as brain abscess and meningitisor encephalitis; infections related to bone diseases such asosteochondritis and osteomyelitis; infections related to cardiovasculardiseases such as endocartitis and pericarditis; or infections related togenitourinary diseases such as epididymitis, prostatitis and urethritis.They can be administered singly, as mixtures of several β-hairpinpeptidomimetics, in combination with other antimicrobial or antibioticagents, or anti cancer agents, or antiviral (e.g. anti-HIV) agents, orin combination with other pharmaceutically active agents. The β-hairpinpeptidomimetics can be administered per se or as pharmaceuticalcompositions.

The β-hairpin peptidomimetics of the invention may be administered perse or may be applied as an appropriate formulation together withcarriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active β-hairpin peptidomimetics intopreparations which can be used pharmaceutically. Proper formulationdepends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solutions may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the β-hairpin peptidomimetics of the invention may be inpowder form for combination with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion by a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aerosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch. The compounds may also be formulated in rectal orvaginal compositions such as suppositories together with appropriatesuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide may also be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent (e.g. for coated stents).Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic agent, additional strategies forprotein stabilization may be employed.

As the β-hairpin peptidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For example, for use as a disinfectant or preservative, anantimicrobially effective amount of a β-hairpin peptidomimetic of theinvention, or a composition thereof, is applied or added to the materialto be desinfected or preserved. By antimicrobially effective amount ismeant an amount of a f-hairpin peptidomimetic of the invention, or acomposition thereof, that inhibits the growth of, or is lethal to, atarget microbe population. While the antimicrobially effective amountwill depend on a particular application, for use as disinfectants orpreservatives the β-hairpin peptidomimetics of the invention, orcompositions thereof, are usually added or applied to the material to bedesinfected or preserved in relatively low amounts. Typically, theβ-hairpin peptidomimetics of the invention comprise less than about 5%by weight of a disinfectant solution or material to be preserved,preferably less than 1% by weight and more preferably less than 0.1% byweight. An ordinary skilled expert will be able to determineantimicrobially effective amounts of particular β-hairpinpeptidomimetics of the invention for particular applications withoutundue experimentation using, for example, the results of the in vitroassays provided in the examples.

For use to treat or prevent microbial infections or diseases related tosuch infections, the β-hairpin peptidomimetics of the invention, orcompositions thereof, are administered or applied in a therapeuticallyeffective amount. By therapeutically effective amount is meant an amounteffective in ameliorating the symptoms of, or in ameliorating, treatingor preventing microbial infections or diseases related thereto.Determination of a therapeutically effective amount is well within thecapacities of those skilled in the art, especially in view of thedetailed disclosure provided herein.

As in the case of disinfectants and preservatives, for topicaladministration to treat or prevent bacterial infections and/or viralinfections a therapeutically effective dose can be determined using, forexample, the results of the in vitro assays provided in the examples.The treatment may be applied while the infection is visible, or evenwhen it is not visible. An ordinary skilled expert will be able todetermine therapeutically effective amounts to treat topical infectionswithout undue experimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skill in the art could readily optimize administration tohumans based on animal data.

Dosage amounts for applications as anti-infective agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the ordinaryskill in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The antimicrobial therapy may be repeated intermittently whileinfections are detectable or even when they are not detectable. Thetherapy may be provided alone or in combination with other drugs, suchas for example anti-HIV agents or anti-cancer agents, or otherantimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the present invention but are not tobe construed as limiting its scope in any way.

Abbreviations

-   -   Ac Acetyl;    -   BSA Bovine serum albumin;    -   Boc tert-Butyloxycarbonyl;    -   DCHA Dicyclohexylamine;    -   DEAD Diethyl azodicarboxylate;    -   DIPEA Diisopropylethylamine;    -   DMEM Dulbecco's Modified Eagle's Medium;    -   DODT 3,6-dioxa-1,8-octanedithiol;    -   FCS Fetal Calf Serum;    -   Fmoc Fluorenylmethyloxycarbonyl;    -   HATU O-(7-Aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate;    -   HBSS Hank's Buffered Salt Solution;    -   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   HCTU O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   Hepes 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;    -   HFIP Hexafluoroisopropanol    -   HOAt 1-Hydroxy-7-azabenzotriazole;    -   IMDM Iscove's Modified Dulbecco's Media;    -   PyBop® (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate;    -   TIS Triisopropylsilane;    -   TPP Triphenylphosphine;    -   RPMI Roswell Park Memorial Institute medium;    -   rt Room temperature.

EXAMPLES

1. Peptide Synthesis

1.1 General Synthetic Procedures

A general method for the synthesis of the peptidomimetics of the presentinvention is exemplified in the following. This is to demonstrate theprincipal concept and does not limit or restrict the present inventionin any way. A person skilled in the art is easily able to modify theseprocedures, especially, but not limited to, choosing a differentstarting position within the ring system, to still achieve thepreparation of the claimed cyclic peptidomimetic compounds of thepresent invention.

Coupling of the First Protected Amino Acid Residue to the Resin

In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1%crosslinked; loading: 1.4 mMol/g) was swollen in dry CH₂Cl₂ for 30 min(7 mL CH₂Cl₂ per g resin). A solution of 0.8 eq of the Fmoc-protectedamino acid and 6 eq of DIPEA in dry CH₂Cl₂/DMF (4/1) (10 mL per g resin)was added. After shaking for 2-4 h at rt the resin was filtered off andwashed successively with CH₂Cl₂, DMF, CH₂Cl₂, DMF and CH₂Cl₂. Then asolution of dry CH₂Cl₂/MeOH/DIPEA (17:2:1) was added (10 mL per gresin). After shaking for 3×30 min the resin was filtered off in apre-weighed sinter funnel and washed successively with CH₂Cl₂, DMF,CH₂Cl₂, MeOH, CH₂Cl₂, MeOH, CH₂Cl₂(2x) and Et₂O (2x). The resin wasdried under high vacuum overnight. The final mass of resin wascalculated before the qualitative control.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared:Fmoc-Dab(Boc)-2-chlorotrityl resin, Fmoc-^(D)Dab(Boc)-2-chlorotritylresin, Fmoc-Lys(Boc)-2-chlorotrityl resin, Fmoc-Trp(Boc)-2-chlorotritylresin, Fmoc-Phe-2-chlorotrityl resin; Fmoc-Val-2-chlorotrityl resin,Fmoc-Pro-2-chlorotrityl resin, Fmoc-Arg(Pbf)-2-chlorotrityl resin andFmoc-Glu(tBu)-2-chlorotrityl resin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out on a Syro-peptide synthesizer(MultiSynTech GmbH) using 24 to 96 reaction vessels. In each vessel 0.04mMol of the above resin were placed and the resin was swelled in CH₂Cl₂and DMF for 15 min, respectively.

The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 1 × 3 min 2 DMF,wash and sweIl 2 × 30 min 3 20% piperidine/DMF 1 × 5 min and 1 × 15 min4 DMF, wash 5 × 1 min 5 3.5 eq Fmoc amino acid/3.5 eq HOAt in DMF + 1 ×40 min 3.5 eq PyBOP/7 eq DIPEA or 3.5 eq DIC 6 3.5 eq Fmoc aminoacid/DMF + 1 × 40 min 3.5 eq HATU or PyBOP or HCTU + 7 eq DIPEA 7 DMF,wash 5 × 1 min 8 20% piperidine/DMF 1 × 5 min and 1 × 15 min 9 DMF, wash5 × 1 min 10 CH₂Cl₂, wash (at the end of the synthesis) 3 × 1 min

Steps 5 to 9 are repeated to add each amino-acid residue.

After the termination of the synthesis of the fully protected peptidefragment, one of the procedures A-E, as described herein below, wasadopted subsequently, depending on which kind of interstrand linkages,as described herein below, were to be formed.

Finally, the peptides were purified by preparative reverse phase LC-MS,as described herein below.

Procedure A: Cyclization and Work Up of a Backbone Cyclized PeptideHaving No Interstrand Linkage

Cleavage, Backbone Cyclization and Deprotection

After assembly of the linear peptide, the resin was suspended in 1 mL of1% TFA in CH₂Cl₂ (v/v; 0.14 mMol) for 3 minutes. After filtration thefiltrate was neutralized with 1 mL of 20% DIPEA in CH₂Cl₂ (v/v; 1.15mMol). This procedure was repeated four times to ensure completion ofthe cleavage. An alternative cleavage method comprises suspension of theresin in 1 mL of 20% HFIP in CH₂Cl₂ (v/v; 1.9 mMol) for 30 minutes,filtration and repetition of the procedure. The resin was washed threetimes with 1 mL of CH₂Cl₂. The CH₂Cl₂ layers containing product wereevaporated to dryness.

The fully protected linear peptide was solubilised in 8 mL of dry DMF.Then 2 eq of HATU and 2 eq of HOAt in dry DMF (1-2 mL) and 4 eq of DIPEAin dry DMF (1-2 mL) were added to the peptide, followed by stirring forca. 16 h. The volatiles were removed by evaporation. The crude cyclicpeptide was dissolved in 7 mL of CH₂Cl₂ and washed three times with 4.5mL 10% acetonitrile in water (v/v). The CH₂Cl₂ layer was then evaporatedto dryness.

To fully deprotect the peptide, 7 mL of cleavage cocktailTFA/DODT/thioanisol/H₂O (87.5:2.5:5:5) or TFA/TIS/H₂O (95:2.5:2.5) wereadded, and the mixture was kept for 2.5-4 h at room temperature untilthe reaction was completed. The reaction mixture was evaporated close todryness, the peptide precipitated with 7 mL of cold Et₂O/pentane andfinally washed 3 times with 4 mL of cold Et₂O/pentane.

Procedures B1 and B2: Cyclization and Work Up of a Backbone CyclizedPeptide Having a Disulfide Interstrand Linkage

B1: Formation of a Disulfide Interstrand Linkage Using DMSO

After cleavage, backbone cyclization and deprotection of the linearpeptide, as described in the corresponding section of procedure A, thedeprotected cyclic peptide was treated with 0.5 mL of DMSO in a solution9.5 mL of H₂O/AcOH (95:5; adjusted to pH=6 with NH₄HCO₃) for 24 h at rtto form the disulfide bridge. Thereafter, the reaction mixture wasevaporated to dryness.

B2: Formation of a Disulfide Interstrand Linkage Using Iodine

Following cleavage and backbone cyclization of the linear peptide, asdescribed in the corresponding section of procedure A, the protectedcyclic peptide was dissolved in 8 mL of 20% HFIP in CH₂Cl₂ (v/v) and asolution of iodine (2 eq) in 2 mL of 20% HFIP in CH₂Cl₂ (v/v) was added.After shaking of the reaction mixture for 1 h, 3 mL of a 1M aqueoussolution of ascorbic acid were added to quench the oxidation reaction.The mixture was shaken for 10 min and after removal of the aqueousphase, the organic phase was washed with 4 mL of water. The organicphase was evaporated to dryness and the deprotection step, as describedin the corresponding section of Procedure A, was performed.

Procedure C: Cyclization and Work Up of a Backbone Cyclized PeptideHaving Two Disulfide Interstrand Linkages

Formation of Two Disulfide Interstrand Linkages

Following cleavage and backbone cyclization of the linear peptide, asdescribed in the corresponding section of procedure A, the protectedcyclic peptide was dissolved in 8 mL of 20% HFIP in CH₂Cl₂ (v/v) and asolution of iodine (2 eq) in 2 mL of 20% HFIP in CH₂Cl₂ (v/v) was added.After shaking of the reaction mixture for 1 h, 3 mL of a 1M aqueoussolution of ascorbic acid were added to quench the oxidation reaction.The mixture was shaken for 10 min and after removal of the aqueousphase, the organic phase was washed with 4 mL of water. The organicphase was evaporated to dryness and the deprotection step, as describedin the corresponding section of Procedure A, was performed.

Procedure D: Cyclization and Work Up of a Backbone Cyclized PeptideHaving a Lactam Interstrand Linkage

Formation of a Lactam Interstrand Linkage

Following assembly of the linear peptide, the resin was swelled in 5 mLof freshly distilled CH₂Cl₂ for at least 15 min. To selectively removealloc- and allyl-protecting groups from amino and carboxyl functionalgroups, respectively, 0.2 eq tetrakis(triphenyl-phosphine)palladium(0)(10 mM) in dry CH₂Cl₂ and 10 eq phenylsilane were added. After shakingthe reaction mixture for 15 min at rt, the resin was filtered off and afresh solution of reagents was added to repeat the procedure. Followingsubsequent washing of the resin with CH₂Cl₂, DMF and Et₂O the resin wasswelled in 5 mL DMF. 1 mL of a DIPEA solution in DMF (24.6 μl DIPEA in 1mL DMF, 4 eq) was added followed by a 1 mL HATU solution in DMF (27.4 mgHATU in DMF, 2 eq). After stirring the reaction mixture overnight theresin was filtered and washed thoroughly with DMF and CH₂Cl₂, Cleavage,backbone cyclization and deprotection of the modified peptide wasperformed as described in the corresponding sections of procedure A.

Procedure E: Cyclization and Work Up of a Backbone Cyclized PeptideHaving a 1,4-Disubstituted 1,2,3-Triazole-Containing Interstrand Linkage

Formation of a 1,4-Disubstituted 1,2,3-Triazole-Containing InterstrandLinkage

Following cleavage, backbone cyclization and deprotection, as describedin the corresponding sections of procedure A, the peptide was purifiedby preparative reverse phase LC-MS, as described herein below. 11 μmolof that purified peptide containing a ω-yne- and a ω-azido-function weredissolved in 12 mL H₂O/tBuOH (1/2, v/v) and 4.4 eq of CuSO₄xSH₂O as wellas 6.6 eq of ascorbic acid were added. The solution was stirredovernight and subsequently evaporated to dryness.

Purification Procedure (Preparative Reverse Phase LC-MS)

Compounds were purified by reverse phase chromatography using aPhenomenex Gemini NX-C18 column, 30×100 mm, 5 μm (Cat No.00D-4435-U0-AX) or a Waters XBridge C18 OBD column, 30×100 mm, 5 μm (CatNo. 186002982).

Mobile phases used were:

A: 0.1% TFA in Water/Acetonitrile 95/5 v/v

B: 0.1% TFA in Acetonitrile

Gradient slopes in the preparative runs were adapted each time based onanalytical LC-MS analysis of the crude product. As an example, a typicalrun was executed using the Phenomenex column with a flow rate of 35mL/min running a gradient from 0-1 min 0% B, at 1.1 min 25% B to a finalof 8 min 45% B (retention time: 5.96 min in this case).

Detection: MS and UV @ 220 nm

Fractions collected were evaporated using a Genevac HT4 evaporator or aBüchi system.

Alternatively for larger amounts the following LC-purification systemwas used:

Column: Waters XBridge C18 OBD column, 50×250 mm, 10 μm (Cat No.186003900)

Mobile phase A: 0.1% TFA in Water

Mobile phase B: Acetonitrile

Flow rate: 150 mL/min

Detection: UV @ 220 nm

After lyophilisation the products were obtained typically as white tooff-white powders and analysed by HPLC-ESI-MS methods as describedbelow. Analytical data after preparative HPLC purification are shown inTable 1.

1.2 Analytical Methods

Analytical method A:

Analytical HPLC retention times (RT, in minutes) were determined usingAscentis Express C8 column, 100×3 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B(CH₃CN+0.085% TFA) and the gradient:0-0.1 min: 95% A, 5% B; 11 min: 15% A, 85% B; 11.02-12.5 min: 3% A, 97%B; 12.55-13.5 min: 95% A, 5% B. Flow rate 1.3 mL/min at 55° C.

Analytical Method B:

Analytical HPLC retention times (RT, in minutes) were determined usingAscentis Express C8 column, 100×3 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B(CH₃CN+0.085% TFA) and the gradient:0-0.1 min: 95% A, 5% B; 7 min: 15% A, 85% B; 7.02 min: 3% A, 97% B;7.02-7.5 min: 3% A, 97% B; 7.52-7.75 min: 95% A, 5% B. Flow rate 1.4mL/min at 55° C.

Analytical Method C:

Analytical HPLC retention times (RT, in minutes) were determined usingAscentis Express C18 column, 50×3 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B(CH₃CN+0.085% TFA) and the gradient:0-0.05 min: 97% A, 3% B; 3.4 min: 45% A, 55% B; 3.45 min-3.65 min: 3% A,97% B; 3.67 min-3.7 min: 97% A, 3% B. Flow rate 1.3 mL/min at 55° C.

Analytical Method D:

Analytical HPLC retention times (RT, in minutes) were determined usingAscentis Express C18 column, 50×3 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B(CH₃CN+0.085% TFA) and the gradient:0-0.05 min: 97% A, 3% B; 4.95-5.35 min: 3% A, 97% B; 5.37-5.4 min: 97%A, 3% B. Flow rate 1.3 mL/min at 55° C.

Analytical Method E:

Analytical HPLC retention times (RT, in minutes) were determined usingAscentis Express C18 column, 50×2.1 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA and B(CH₃CN+0.085% TFA) and the gradient:0-0.05 min: 97% A, 3% B; 3.3 min: 15% A, 85% B; 3.32 min: 3% A, 97% B;3.32-3.55 min: 3% A, 97% B; 3.57-3.7 min: 97% A, 3% B. Flow rate 1.6mL/min at 55° C. 1.3 Synthesis of peptide sequences

Examples 1, 35 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid (S)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-Dab(Boc)-2-chlorotrityl resin). Thelinear peptides were synthesized on the solid support according to theprocedure described above in the following sequence:Resin-Dab-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷. After cleavage fromresin, backbone cyclization and deprotection, the disulfide interstrandlinkages were formed as indicated in procedure B1. Finally, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex. 1, 35in Table 1.

Examples 2, 3, 36-37 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid (R)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-^(D)Dab(Boc)-2-chlorotrityl resin).The linear peptides were synthesized on the solid support according tothe procedure described above in the following sequence:Resin-^(D)Dab-P⁵-P⁴-P²-P²-P¹-T¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷. Aftercleavage from resin, backbone cyclization and deprotection, thedisulfide interstrand linkages were formed as indicated in procedure B1.Finally, the peptides were purified by preparative reverse phase LC-MS,as described above. After lyophilisation the products were obtained aswhite to off-white powders and characterised by HPLC-MS. For analyticaldata, see Ex. 2, 3, 36-37 in Table 1.

Examples 4-9, 38 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid (S)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-Dab(Boc)-2-chlorotrityl resin). Thelinear peptides were synthesized on the solid support according to theprocedure described above in the following sequence:Resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸. After cleavage fromresin, backbone cyclization and deprotection, the disulfide interstrandlinkages were formed as indicated in procedure B1. Finally, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex. 4-9,38 in Table 1.

Examples 10-18, 20-23, 33 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Trp(Boc)-OH, which was grafted to the resin(Fmoc-Trp(Boc)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Trp-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹. After cleavage fromresin, backbone cyclization and deprotection, the disulfide interstrandlinkages were formed as indicated in procedure B1. Finally, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex.10-18, 20-23, 33 in Table 1.

Example 19 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid Fmoc-Phe-OH, which was grafted to the resin(Fmoc-Phe-2-chlorotrityl resin). The linear peptide was synthesized onthe solid support according to the procedure described above in thefollowing sequence: Resin-Phe-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P²-P¹-P¹⁰-P⁹.After cleavage from resin, backbone cyclization and deprotection, thedisulfide interstrand linkage was formed as indicated in procedure B1.Finally, the peptide was purified by preparative reverse phase LC-MS, asdescribed above. After lyophilisation the product was obtained as whiteto off-white powders and characterised by HPLC-MS. For analytical data,see Ex. 19 in Table 1.

Examples 24-25, 39-40 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Arg(Pbf)-OH, which was grafted to the resin(Fmoc-Arg(Pbf)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Arg-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹. After cleavage fromresin, backbone cyclization and deprotection, the disulfide interstrandlinkages were formed as indicated in procedure B1. Finally, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex.24-25, 39-40 in Table 1.

Example 51 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid Fmoc-Dab(Boc)-OH, which was grafted to the resin(Fmoc-Dab(Boc)-2-chlorotrityl resin). The linear peptide was synthesizedon the solid support according to the procedure described above in thefollowing sequence: Resin-Dab-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶P⁵-P⁴-P³-P²-P¹.After cleavage from resin and backbone cyclization the disulfideinterstrand linkage was formed as indicated in procedure B2. Afterdeprotection the peptide was purified by preparative reverse phaseLC-MS, as described above. After lyophilisation the product was obtainedas white to off-white powder and characterised by HPLC-MS. Foranalytical data, see Ex. 51 in Table 1.

Examples 52-54, 73, 78-79 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Trp(Boc)-OH, which was grafted to the resin(Fmoc-Trp(Boc)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Trp-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹. After cleavage fromresin and backbone cyclization the disulfide interstrand linkage wasformed as indicated in procedure B2. After deprotection the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowder and characterised by HPLC-MS. For analytical data, see Ex. 52-54,73, 78-79 in Table 1.

Examples 55-66, 69-72, 74 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Arg(Pbf)-OH, which was grafted to the resin(Fmoc-Arg(Pbf)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Arg-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹. After cleavage fromresin and backbone cyclization the disulfide interstrand linkages wereformed as indicated in procedure B2. After deprotection the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex.55-66, 69-72, 74 in Table 1.

Example 67 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid Fmoc-Lys(Boc)-OH, which was grafted to the resin(Fmoc-Lys(Boc)-2-chlorotrityl resin). The linear peptide was synthesizedon the solid support according to the procedure described above in thefollowing sequence: Resin-Lys-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹.After cleavage from resin and backbone cyclization the disulfideinterstrand linkage was formed as indicated in procedure B2. Afterdeprotection the peptide was purified by preparative reverse phaseLC-MS, as described above. After lyophilisation the product was obtainedas white to off-white powder and characterised by HPLC-MS. Foranalytical data, see Ex. 67 in Table 1.

Example 68 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid Fmoc-Val-OH, which was grafted to the resin(Fmoc-Val-2-chlorotrityl resin). The linear peptide was synthesized onthe solid support according to the procedure described above in thefollowing sequence: Resin-Val-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹.After cleavage from resin and backbone cyclization the disulfideinterstrand linkage was formed as indicated in procedure B2. Afterdeprotection the peptide was purified by preparative reverse phaseLC-MS, as described above. After lyophilisation the product was obtainedas white to off-white powder and characterised by HPLC-MS. Foranalytical data, see Ex. 68 in Table 1.

Examples 42-43 are shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid Fmoc-Arg(Pbf)-OH, which was grafted to the resin(Fmoc-Arg(Pbf)-2-chlorotrityl resin). The linear peptide was synthesizedon the solid support according to the procedure described above in thefollowing sequence: Resin-Arg-T-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹.After cleavage from resin and backbone cyclization the disulfideinterstrand linkages were formed as indicated in procedure C. Afterdeprotection the peptide was purified by preparative reverse phaseLC-MS, as described above. After lyophilisation the product was obtainedas white to off-white powder and characterised by HPLC-MS. Foranalytical data, see Ex. 42-43 in Table 1.

Examples 26-32, 41 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid (S)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-Dab(Boc)-2-chlorotrityl resin). Thelinear peptides were synthesized on the solid support according to theprocedure described above in the following sequence:Resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸. Then the lactaminterstrand linkages were formed as indicated in procedure D. Aftercleavage from resin, backbone cyclization and deprotection, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex.26-32, 41 in Table 1.

Examples 75-77 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Glu(tBu)-OH, which was grafted to the resin(Fmoc-Glu(tBu)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Glu-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³. Then the lactaminterstrand linkages were formed as indicated in procedure D. Aftercleavage from resin, backbone cyclization and deprotection, the peptideswere purified by preparative reverse phase LC-MS, as described above.After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex. 75-77in Table 1.

Example 34 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid L-proline, which was grafted to the resin(Fmoc-Pro-2-chlorotrityl resin). The linear peptide was synthesized onthe solid support according to the procedure described above in thefollowing sequence: Resin-Pro-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹.Following cleavage, backbone cyclization and deprotection, the peptidewas purified by preparative reverse phase LC-MS and thereafter, the1,4-disubstituted 1,2,3-triazole-containing interstrand linkage wasformed as indicated in procedure E. The peptide was purified bypreparative reverse phase LC-MS, as described above, and lyophilized.The product was obtained as white to off-white powders and characterisedby HPLC-MS. For analytical data, see Ex. 34 in Table 1.

Examples 44-46 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid (S)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-Dab(Boc)-2-chlorotrityl resin). Thelinear peptides were synthesized on the solid support according to theprocedure described above in the following sequence:Resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸. After cleavage fromresin, backbone cyclization and deprotection, as indicated in procedureA, the peptides were purified by preparative reverse phase LC-MS, asdescribed above. After lyophilisation the products were obtained aswhite to off-white powders and characterised by HPLC-MS. For analyticaldata, see Ex. 44-46 in Table 1.

Examples 47-49 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid Fmoc-Trp(Boc)-OH, which was grafted to the resin(Fmoc-Trp(Boc)-2-chlorotrityl resin). The linear peptides weresynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-Trp-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹. After cleavage fromresin, backbone cyclization and deprotection, as indicated in procedureA, the peptides were purified by preparative reverse phase LC-MS, asdescribed above. After lyophilisation the products were obtained aswhite to off-white powders and characterised by HPLC-MS. For analyticaldata, see Ex. 47-49, in Table 1.

Example 50 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid L-proline, which was grafted to the resin(Fmoc-Pro-2-chlorotrityl resin). The linear peptide was synthesized onthe solid support according to the procedure described above in thefollowing sequence: Resin-Pro-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹.After cleavage from resin, backbone cyclization and deprotection, asindicated in procedure A, the peptide was purified by preparativereverse phase LC-MS, as described above. After lyophilisation theproduct was obtained as white to off-white powders and characterised byHPLC-MS. For analytical data, see Ex. 50 in Table 1.

1.4 Sequence Data

TABLE 1 Examples (Ex.) Ex.^(c)) P^(1a)) P^(2a)) P^(3a)) P^(4a)) P^(5a))P^(6a)) P^(7a)) P^(8a)) P^(9a)) P^(10a)) 1 Leu Cys Tyr Ala Dab Dab DabTrp Ala Val 2 Leu Cys Tyr Ala Dab ^(D)Dab Dab Trp Ala Val 3 Leu Cys TyrAla Orn ^(D)Dab Dab Trp Ala Val 4 Leu Cys Tyr Asn Orn ^(D)Dab Dab LeuSer tBuGly 5 Ile Cys Tyr Asn Orn ^(D)Dab Dab Leu Ser Val 6 Leu Cys TyrAsn Orn ^(D)Dab Dab Trp Ser tBuGly 7 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 8 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 9 Val Cys Tyr DabDap ^(D)Dab Dab Trp Dab tBuGly 10 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 11 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 12 Ile Cys TyrDab Orn ^(D)Dab Dab Trp Dab tBuGly 13 Ile Cys Tyr Dab Orn ^(D)Dab DabTrp Dab tBuGly 14 Ile Cys Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly 15 ValCys Tyr Dab Dap Dab Dab Trp Dab tBuGly 16 Ile Cys Tyr Dab Orn ^(D)DabDab Trp Dab tBuGly 17 Leu Cys Tyr Ala Orn ^(D)Dab Dab Trp Ala Tyr 18 LeuCys Val Asn Orn ^(D)Dab Dab Trp Ser Tyr 19 Leu Cys Tyr Ala Orn ^(D)DabDab Phe Ala Tyr 20 Leu Cys Val Val Orn ^(D)Dab Dab Trp Tyr Tyr 21 LeuCys Tyr Val Orn ^(D)Dab Dab Trp Tyr Tyr 22 Leu Cys Tyr Val Orn ^(D)DabDab Trp Tyr Tyr 23 Leu Cys Tyr Ala Orn ^(D)Dab Dab Trp Ala Tyr 24 PheCys Val Thr Orn ^(D)Dab Dab Trp Thr Tyr 25 Leu Cys Val Thr Orn ^(D)DabDab Trp Thr Tyr 26 Leu Dab Tyr Dab Dab Dab Dab Trp Dab tBuGly 27 Val DabTyr Dab Dap ^(D)Dab Dab Trp Dab tBuGly 28 Val Dab Tyr Dab Dap ^(D)DabDab Trp Dab Val 29 Val Dab Tyr Dab Dap ^(D)Dab Dab Trp Dab tBuGly 30 ValDab Tyr Dab Dab ^(D)Dab Dab Trp Dab tBuGly 31 Val Dab Tyr Dab Dap^(D)Dab Dab Trp Dap tBuGly 32 Val Dab Tyr Dab Dab Dab Dab Trp Dab tBuGly33 Leu Pen tBuGly Dab Orn ^(D)Dab Dab Trp Dab Chg 34 Val Pra Tyr Dab Dap^(D)Dab Dab Trp Dab tBuGly 35 Leu Thr Tyr Cys Dab Dab Dab Trp Cys Val 36Leu Thr Tyr Cys Dab ^(D)Dab Dab Trp Cys Val 37 Leu Thr Tyr Cys Dab^(D)Dab Dab Trp Cys Val 38 Leu Ser Tyr Cys Orn ^(D)Dab Dab Trp Cys Tyr39 Leu Ser Tyr Cys Orn ^(D)Dab Dab Phe Cys Val 40 Leu Ser Tyr Cys OrnGly Dab Trp Cys Val 41 Leu Tyr Tyr Dab Orn ^(D)Dab Dab Trp Asp tBuGly 42Leu Cys Tyr Cys Dab Dab Dab Trp Cys Tyr 43 Leu Cys Tyr Cys Dab ^(D)DabDab Trp Cys Tyr 44 Val Ser Tyr Dab Dap ^(D)Dab Dab Trp Dab tBuGly 45 ValDap Tyr Dab Dap ^(D)Dab Dab Trp Dab tBuGly 46 Val Dap Tyr Dab Dab^(D)Dab Dab Trp Dab tBuGly 47 Ile Thr Tyr Dab Orn ^(D)Dab Dab Trp DabtBuGly 48 Ile Thr Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly 49 Ile Thr TyrDab Orn ^(D)Dab Dab Trp Dab tBuGly 50 Phe Dap Tyr Dab Orn ^(D)Dab DabTrp Dab tBuGly 51 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 52 Leu CysTyr Ser Orn ^(D)Dab Dab Trp Asn Tyr 53 Leu Cys Tyr Asn Orn ^(D)Dab DabTrp Asn Tyr 54 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Asn Tyr 55 Leu CysTyr Asn Orn Dab Dab Trp Ser Tyr 56 Leu Cys Tyr Asn Dab ^(D)Dab Dab TrpSer Tyr 57 Val Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 58 Cpa Cys TyrAsn Orn ^(D)Dab Dab Trp Ser Tyr 59 Cpg Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 60 Nva Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 61 Abu Cys TyrAsn Orn ^(D)Dab Dab Trp Ser Tyr 62 Leu Cys Tyr Gln Orn ^(D)Dab Dab TrpSer Tyr 63 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 64 Leu Cys TyrAsn Orn ^(D)Dab Dab Trp Ser Tyr 65 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 66 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 67 Leu Cys TyrAsn Orn ^(D)Dab Dab Trp Ser Tyr 68 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 69 Val Cys Tyr Asn Orn ^(D)Dab Dab Trp Ser Tyr 70 Ile Cys TyrAsn Orn ^(D)Dab Dab Trp Ser Tyr 71 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 72 Leu Cys Tyr Dap Orn ^(D)Dab Dab Trp Ser Tyr 73 Leu Cys TyrDab Orn ^(D)Dab Dab Trp Asn Tyr 74 Leu Cys Tyr Asn Orn ^(D)Dab Dab TrpSer Tyr 75 Leu Asp Tyr Asn Orn ^(D)Dab Dab Trp Ser tBuGly 76 Leu Asp TyrAsn Orn ^(D)Dab Dab Trp Ser tBuGly 77 Leu Asp Tyr Dab Orn ^(D)Dab DabTrp Dab Tyr 78 Leu Cys Tyr Asn Orn ^(D)Dab Dab Trp Dab Tyr 79 Leu CysTyr Asn Orn ^(D)Dab Dab Trp Dab Tyr Analyt. RT Purity Ex.^(c)) P^(11a))P^(12a)) T^(1a)) T^(2a)) Meth. MS^(b)) [min] [%] 1 Cys Val ^(D)Pro Arg C780.8 2.0 92 2 Cys Val ^(D)Pro Arg C 780.8 2.03 85 3 Cys Val ^(D)Pro ArgC 788.3 2.02 92 4 Cys Val ^(D)Dab Arg B 798.5 2.45 84 5 Cys Tyr ^(D)DabArg B 814.4 2.12 87 6 Cys Thr ^(D)Dab Dab B 798.9 2.04 82 7 Cys Thr^(D)Dab Dab B 824.4 1.81 81 8 Cys Ser ^(D)Dab Dab B 817.0 1.74 85 9 CysSer NMeAla Pro B 761.3 2.39 95 10 Cys Val ^(D)Dab Arg A 851.5 3.78 86 11Cys Tyr ^(D)Dab Arg A 883.4 3.60 90 12 Cys Ser ^(D)Dab Arg B 819.9 1.9690 13 Cys Ser ^(D)Dab Ala B 777.3 2.02 90 14 Cys Ser ^(D)Dab Pro B 790.32.13 79 15 Cys Thr ^(D)Tyr Pro B 807.4 2.64 95 16 Cys Ser ^(D)Ala Tyr B808.4 2.34 94 17 Cys Tyr ^(D)Dab Arg A 853.8 3.72 91 18 Cys Val ^(D)DabArg A 819.5 3.99 92 19 Cys Val ^(D)Dab Arg D 802.0 1.67 91 20 Cys Val^(D)Dab Arg A 850.0 4.09 95 21 Cys Val ^(D)Dab Arg A 881.9 3.84 90 22Cys Tyr ^(D)Dab Arg A 914.1 3.70 91 23 Cys Val ^(D)Dab Arg E 821.7 1.1184 24 Cys Dab ^(D)Dab Arg A 837.5 3.04 89 25 Cys Val ^(D)Dab Arg A 819.44.05 91 26 Asp Ser ^(D)Ala Pro B 764.9 2.48 85 27 Asp Ser ^(D)Ala Pro B750.9 2.38 95 28 Asp Thr ^(D)Ala Pro B 750.9 2.43 83 29 Asp Thr ^(D)ThrPro B 773.0 1.47 95 30 Asp Ser ^(D)Ala Ala B 744.9 2.20 92 31 Asp Ser^(D)Ala Tyr B 776.9 2.30 95 32 Asp Ser Sar Pro B 757.9 3.08 88 33 PenSer ^(D)Pro Pro B 804.9 4.01 95 34 Abu(4N₃) Ser ^(D)Pro Pro B 775.9 2.2691 35 Thr Val ^(D)Pro Arg C 810.8 1.89 95 36 Thr Val ^(D)Pro Arg C 810.81.93 91 37 Thr Val ^(D)Pro Dab C 782.8 1.89 92 38 Ala Ser ^(D)Dab Dab B795.5 1.79 86 39 Ser Val ^(D)Dab Arg A 786.5 4.06 84 40 Ala Val ^(D)DabArg E 775.8 1.16 89 41 Val Ser ^(D)Dab Pro B 817.8 2.42 95 42 Cys Val^(D)Pro Arg C 843.8 1.96 90 43 Cys Val ^(D)Pro Arg C 843.8 1.97 94 44Ala Ser ^(D)Pro NMeAla B 738.4 2.42 95 45 Ser Thr ^(D)Ala Pro B 746.02.47 95 46 Ser Thr ^(D)Ala Pro B 752.9 2.45 95 47 Ala Ser ^(D)Pro Tyr B805.4 2.48 88 48 Ala Ser ^(D)Dab Pro A 773.9 2.92 95 49 Ala Ser ^(D)AlaTyr B 792.4 2.41 94 50 Ala Ser ^(D)Dab Pro B 783.8 2.19 93 51 Cys Val^(D)Dab Dab B 822.9 2.18 93 52 Cys Val ^(D)Dab Arg B 850.9 2.25 91 53Cys Val ^(D)Dab Arg B 864.6 2.21 78 54 Cys Val ^(D)Dab Dab B 836.9 2.1780 55 Cys Val ^(D)Dab Arg B 851.4 2.16 95 56 Cys Val ^(D)Dab Arg B 843.92.27 92 57 Cys Val ^(D)Dab Arg B 843.9 2.07 89 58 Cys Val ^(D)Dab Arg B863.9 2.35 90 59 Cys Val ^(D)Dab Arg B 856.9 2.18 95 60 Cys Val ^(D)DabArg B 844.4 2.11 90 61 Cys Val ^(D)Dab Arg B 836.9 2.00 87 62 Cys Val^(D)Dab Arg B 858.4 2.25 84 63 Cys Leu ^(D)Dab Arg B 858.4 2.36 94 64Cys tBuGly ^(D)Dab Arg B 857.9 2.36 94 65 Cys Val ^(D)Lys Arg B 865.12.27 91 66 Cys Val ^(D)Arg Arg B 879.1 2.30 89 67 Cys Val ^(D)Dab Lys B836.9 2.22 85 68 Cys Val ^(D)Dab Dap B 815.9 2.19 95 69 Cys Leu ^(D)DabArg B 851.4 2.20 92 70 Cys Val ^(D)Dab Arg B 851.4 2.17 91 71 Cys Ala^(D)Dab Arg B 836.9 2.01 88 72 Cys Val ^(D)Dab Arg B 837.0 2.26 86 73Cys Val ^(D)Ala Arg B 843.4 2.45 86 74 Cys Thr ^(D)Dab Arg B 851.9 1.8887 75 Dab Thr ^(D)Dab Arg B 823.5 2.07 81 76 Dab Thr ^(D)Dab Dab B 796.02.02 78 77 Dab Ser ^(D)Ala Pro B 796.9 2.22 91 78 Cys Val ^(D)Pro Arg B855.9 2.53 91 79 Cys Val ^(D)Ala Arg B 843.5 2.46 84 ^(a))Abbreviationsof amino acid see listing above. ^(b))MS: either [M + 2H]²⁺ or [M +3H]³⁺. ^(c))The sequences of Examples 1-25, 33 and 51-79 have disulfidelinkages between P² and P¹¹, as described above; the sequences ofExamples 26-32 have lactam linkages between P² and P¹¹, as describedabove; the sequence of Example 34 has a 1,2,3-triazole linkage betweenP² and P¹¹, as described above; the sequences of Examples 35-40 havedisulfide linkages, the sequence of Ex 41 has a lactam linkage betweenP⁴ and P⁹, as described above; and the sequences of Examples 42, 43 havedisulfide linkages between both P² and P¹¹, and P⁴ and P⁹, as describedabove.

2. Biological Methods

2.1. Preparation of the Peptides

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mg/mL. Stocksolutions were kept at +4° C., light protected.

2.2. Antimicrobial Activity of the Peptides

The selective antimicrobial activities of the peptides were determinedin 96-well plates (Greiner, polystyrene) by the standard NCCLS brothmicrodilution method (National Committee for Clinical LaboratoryStandards 1993. Methods for dilution antimicrobial susceptibility testsfor bacteria that grow aerobically, 3rd ed. Approved standard M7-A6;National Committee for Clinical laboratory standards, Wayne, Pa.) withslight modifications. Inocula of the microorganisms were diluted intoMueller-Hinton II (MH, cation adjusted) broth and compared with a 0.5McFarland standard to give appr. 10⁶ colony forming units (CFU)/mL.Aliquots (90 μl) of inoculate were added to 10 μl of MH broth+P-80(Polysorbate 80, 0.002% final concentration) containing the peptide inserial two-fold dilutions. The following microorganisms were used todetermine antibiotic selectivity of the peptides: Escherichia coli ATCC25922, Klebsiella pneumoniae ATCC 13883 and Acinetobacter baumannii DSM30008. Antimicrobial activities of the peptides were expressed as theminimal inhibitory concentration (MIC) in μg/mL at which no visiblegrowth was observed after 18-20 hours of incubation at 35° C.

2.3. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) and centrifuged for 5 min at 3000×g. Compounds(100 μg/mL) were incubated with 20% hRBC (v/v) for 1 h at 37° C. andshaking at 300 rpm. The final erythrocyte concentration wasapproximately 0.9×10⁹ cells/mL. A value of 0% and 100% cell lyses,respectively, was determined by incubation of hRBC in the presence ofPBS containing 0.001% acetic acid and 2.5% Triton X-100 in H₂O,respectively. The samples were centrifuged, the supernatants were 8-folddiluted in PBS buffer and the optical densities (OD) were measured at540 nm. The 100% lyses value (OD₅₄₀H₂O) gave an OD₅₄₀ of approximately0.5-1.0.

Percent hemolysis was calculated as follows:(OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

The results of the experiments described in 2.2-2.3 are indicated inTable 2 herein below.

TABLE 2 Minimal inhibitory concentrations (MIC) in Muller-Hinton brothII and hemolysis Escherichia Klebsiella Acinetobacter coli pneumoniaebaumannii Hemolysis ATCC 25922 ATCC 13883 DSM 30008 at MIC MIC MIC 100μg/mL Ex. [μg/mL] [μg/mL] [μg/mL] [%] 1 2 1 0.75 5 2 4 2 2.5 5 3 2 1 1 44 0.75 0.5 0.25 4 5 0.5 0.25 0.25 4 6 0.5 0.5 0.5 5 7 2 1 2 1 8 1 0.51.5 1 9 0.5 0.5 1 2 10 0.5 1 0.5 1 11 0.25 0.25 0.5 4 12 0.5 1 1 1 130.5 8 2 1 14 0.5 1 1 1 15 0.5 0.25 0.5 2 16 0.5 0.5 1 1 17 0.5 1 0.5 418 0.5 0.5 0.25 8 19 0.5 1 1 1 20 1 1 0.25 7 21 1 1 0.5 6 22 0.5 1 0.5 623 2 1 0.75 1 24 1 2 2 0 25 1 1 0.25 3 26 2 1 2 1 27 0.5 0.5 1 2 28 1 12 1 29 0.5 0.5 1 2 30 1 2 8 1 31 1 1 4 1 32 2 1 4 1 33 1 2 1 1 34 4 2 40 35 2 2 1 4 36 4 2 2 2 37 4 2 2 2 38 2 2 3 1 39 0.5 0.25 0.5 4.5 40 4 24 4 41 2 1 2 2 42 4 2 1 3 43 4 2 1 2 44 1 0.5 2 1 45 0.5 0.25 1 4 46 10.5 1 0 47 1 1 4 0 48 1 2 8 1 49 2 2 4 2 50 1 0.5 2 11 51 0.75 0.75 0.752 52 0.75 1.5 1.25 1 53 1 1 1.5 1 54 0.75 1 1.25 3 55 1 1 1.25 0 56 1 10.625 1 57 1 1.5 1.25 1 58 0.5 0.75 0.625 3 59 1 0.75 0.75 1 60 1 1 0.751 61 2 2 1.5 1 62 0.375 1 0.625 2 63 1 0.75 0.625 3 64 1 1 1.125 1 65 21 1.25 1 66 1 0.5 1.25 2 67 1 1 1.5 1 68 0.75 0.5 1.25 1 69 1 1 1 1 70 11 2.25 1 71 1.5 1 1.5 1 72 0.75 0.5 0.625 3 73 0.75 1 1.5 1 74 4 1 1.5 175 1.5 1 1.5 1 76 1 1 1.5 2 77 1.5 2 3 1 78 1.5 1 1.5 1 79 1 1 1.5 1

The invention claimed is:
 1. A method of treating infections byGram-negative bacteria, the method comprising administering to a subjectin need thereof a pharmaceutically acceptable amount of a compound orpharmaceutical composition, wherein the Gram-negative infections arerespiratory infections, skin or soft tissue infections, gastrointestinalinfections, eye infections, ear infections, CNS infections, boneinfections, cardiovascular infections, or genitourinary infections; andwherein the compound is a compound of the general formula (I) or apharmaceutically acceptable salt thereof,cyclo[P¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²]  (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement; and wherein the compound is selected from the group consistingof β-hairpin peptidomimetics of general formula (I) having a disulfidelinkage; a lactam linkage; or a 1,2,3-triazole linkage between P² andP¹¹: cyclo(-Leu-Cys-Tyr-Ala-Dab-Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Dab-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-tBuGly-Cys-Val-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-Val-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ser-^(D)Dab-Dab-); cyclo(-Val-Cys-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-NMeAla-Pro-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Ala-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Pro-);cyclo(-Val-Cys-Tyr-Dab-Dap-Dab-Dab-Trp-Dab-tBuGly-Cys-Thr-^(D)Tyr-Pro-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Ala-Tyr-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Phe-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Phe-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Dab-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Ser-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Dab-); cyclo(-Leu-Cys-Tyr-Asn-Orn-Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Dab-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpa-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpg-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Nva-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Abu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Gln-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-tBuGly-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Lys-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Arg-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Lys-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dap-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ala-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dap-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Ala-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Ala-Arg-);cyclo(-Leu-Pen-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Pen-Ser-^(D)Pro-Pro-); cyclo(-Leu-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-Val-Asp-Thr-^(D)Ala-Pro-); cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Thr-^(D)Thr-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Ala-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dap-tBuGly-Asp-Ser-^(D)Ala-Tyr-);cyclo(-Val-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab- tBuGly-Asp-Ser-Sar-Pro-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Arg-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Dab-);cyclo(-Leu-Asp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Dab-Ser-^(D)Ala-Pro-); cyclo(-Val-Pra-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Abu(4N₃)-Ser-^(D)Pro-Pro-);

or a pharmaceutically acceptable salt thereof; and/or the groupconsisting of β-hairpin peptidomimetics of general formula (I) having adisulfide linkage; or a lactam linkage between P⁴ and P⁹; or disulfidelinkages between P² and P¹¹, and P⁴ and P⁹:cyclo(-Leu-Thr-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Val- Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Trp-Cys-Tyr-Ala-Ser-^(D)Dab-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Phe-Cys-Val-Ser-Val-^(D)Dab-Arg-); cyclo(-Leu-Ser-Tyr-Cys-Orn-Gly-Dab-Trp-Cys-Val-Ala-Val-^(D)Dab-Arg-); cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asp-tBuGly-Val-Ser-^(D)Dab-Pro-);cyclo(-Leu-Cys-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Tyr- Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Tyr-Cys-Val-^(D)Pro-Arg-);

or a pharmaceutically acceptable salt thereof; and/or the groupconsisting of β-hairpin peptidomimetics of general formula (I)cyclo(-Val-Ser-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-NMeAla-);cyclo(-Val-Dap-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Val-Dap-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Tyr-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Ala-Tyr-);cyclo(-Phe-Dap-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);

or a pharmaceutically acceptable salt thereof; wherein saidpharmaceutical composition contains said compound of the general formula(I) or a mixture of compounds of general formula (I) and at least onepharmaceutically inert carrier.
 2. A method of treating an infection byGram-negative bacteria, the method comprising administering to a subjectin need thereof a pharmaceutically acceptable amount of a compound orpharmaceutical composition, wherein the infection is a nosocomialinfection, a catheter-related infection, a non-catheter-relatedinfection, a urinary tract infection, or a bloodstream infection,wherein the compound is a compound of the general formula (I) or apharmaceutically acceptable salt thereof,cyclo[P¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²]  (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement, and wherein the compound is selected from the group consistingof β-hairpin peptidomimetics of general formula (I) having a disulfidelinkage; a lactam linkage; or a 1,2,3-triazole linkage between P² andP¹¹: cyclo(-Leu-Cys-Tyr-Ala-Dab-Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Dab-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Val-Cys-Val-^(D)Pro-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-tBuGly-Cys-Val-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Leu-Ser-Val-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ser-^(D)Dab-Dab-); cyclo(-Val-Cys-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-NMeAla-Pro-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Tyr-^(D)Dab-Arg-); cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Ala-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Dab-Pro-);cyclo(-Val-Cys-Tyr-Dab-Dap-Dab-Dab-Trp-Dab-tBuGly-Cys-Thr-^(D)Tyr-Pro-);cyclo(-Ile-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Cys-Ser-^(D)Ala-Tyr-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Phe-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Val-Orn-^(D)Dab-Dab-Trp-Tyr-Tyr-Cys-Tyr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Ala-Orn-^(D)Dab-Dab-Trp-Ala-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Phe-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Dab-^(D)Dab-Arg-);cyclo(-Leu-Cys-Val-Thr-Orn-^(D)Dab-Dab-Trp-Thr-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dab-);cyclo(-Leu-Cys-Tyr-Ser-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Dab-Dab-); cyclo(-Leu-Cys-Tyr-Asn-Orn-Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Dab-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpa-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Cpg-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Nva-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Abu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Gln-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-tBuGly-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Lys-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Arg-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Lys-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Dap-);cyclo(-Val-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Leu-^(D)Dab-Arg-);cyclo(-Ile-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Ala-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dap-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Val-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asn-Tyr-Cys-Val-^(D)Ala-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-Tyr-Cys-Thr-^(D)Dab-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Cys-Val-^(D)Ala-Arg-);cyclo(-Leu-Pen-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Pen-Ser-^(D)Pro-Pro-); cyclo(-Leu-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-Val-Asp-Thr-^(D)Ala-Pro-); cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Thr-^(D)Thr-Pro-);cyclo(-Val-Dab-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Asp-Ser-^(D)Ala-Ala-);cyclo(-Val-Dab-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dap-tBuGly-Asp-Ser-^(D)Ala-Tyr-);cyclo(-Val-Dab-Tyr-Dab-Dab-Dab-Dab-Trp-Dab- tBuGly-Asp-Ser-Sar-Pro-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Arg-);cyclo(-Leu-Asp-Tyr-Asn-Orn-^(D)Dab-Dab-Trp-Ser-tBuGly-Dab-Thr-^(D)Dab-Dab-);cyclo(-Leu-Asp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Tyr-Dab-Ser-^(D)Ala-Pro-); cyclo(-Val-Pra-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Abu(4N₃)-Ser-^(D)Pro-Pro-);

or a pharmaceutically acceptable salt thereof; and/or the groupconsisting of β-hairpin peptidomimetics of general formula (I) having adisulfide linkage; or a lactam linkage between P⁴ and P⁹; or disulfidelinkages between P² and P¹¹, and P⁴ and P⁹:cyclo(-Leu-Thr-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Val- Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Arg-);cyclo(-Leu-Thr-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Val-Thr-Val-^(D)Pro-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Trp-Cys-Tyr-Ala-Ser-^(D)Dab-Dab-);cyclo(-Leu-Ser-Tyr-Cys-Orn-^(D)Dab-Dab-Phe-Cys-Val-Ser-Val-^(D)Dab-Arg-); cyclo(-Leu-Ser-Tyr-Cys-Orn-Gly-Dab-Trp-Cys-Val-Ala-Val-^(D)Dab-Arg-); cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Asp-tBuGly-Val-Ser-^(D)Dab-Pro-);cyclo(-Leu-Cys-Tyr-Cys-Dab-Dab-Dab-Trp-Cys-Tyr- Cys-Val-^(D)Pro-Arg-);cyclo(-Leu-Cys-Tyr-Cys-Dab-^(D)Dab-Dab-Trp-Cys-Tyr-Cys-Val-^(D)Pro-Arg-);

or a pharmaceutically acceptable salt thereof; and/or the groupconsisting of β-hairpin peptidomimetics of general formula (I)cyclo(-Val-Ser-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-NMeAla-);cyclo(-Val-Dap-Tyr-Dab-Dap-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Val-Dap-Tyr-Dab-Dab-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Thr-^(D)Ala-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Tyr-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);cyclo(-Ile-Thr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Ala-Tyr-);cyclo(-Phe-Dap-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Dab-Pro-);

or a pharmaceutically acceptable salt thereof; wherein said compositioncontains said compound of the general formula (I) or a mixture ofcompounds of general formula (I) and at least one pharmaceutically inertcarrier.